The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles
Identifieur interne : 002987 ( Pmc/Corpus ); précédent : 002986; suivant : 002988The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles
Auteurs : J. Des Parkin ; James D. San Antonio ; Anton V. Persikov ; Hayat Dagher ; Raymond Dalgleish ; Shane T. Jensen ; Xavier Jeunemaitre ; Judy SavigeSource :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
Collagen III is critical to the integrity of blood vessels and distensible organs, and in hemostasis. Examination of the human collagen III interactome reveals a nearly identical structural arrangement and charge distribution pattern as for collagen I, with cell interaction domains, fibrillogenesis and enzyme cleavage domains, several major ligand-binding regions, and intermolecular crosslink sites at the same sites. These similarities allow heterotypic fibril formation with, and substitution by, collagen I in embryonic development and wound healing. The collagen III fibril assumes a “flexi-rod” structure with flexible zones interspersed with rod-like domains, which is consistent with the molecule’s prominence in young, pliable tissues and distensible organs. Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2β1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with
Url:
DOI: 10.1371/journal.pone.0175582
PubMed: 28704418
PubMed Central: 5509119
Links to Exploration step
PMC:5509119Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles</title><author><name sortKey="Parkin, J Des" sort="Parkin, J Des" uniqKey="Parkin J" first="J. Des" last="Parkin">J. Des Parkin</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="San Antonio, James D" sort="San Antonio, James D" uniqKey="San Antonio J" first="James D." last="San Antonio">James D. San Antonio</name><affiliation><nlm:aff id="aff002"><addr-line>Operations, Stryker Global Quality and Operations, Malvern, PA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Persikov, Anton V" sort="Persikov, Anton V" uniqKey="Persikov A" first="Anton V." last="Persikov">Anton V. Persikov</name><affiliation><nlm:aff id="aff003"><addr-line>Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Lab, Princeton, NJ, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dagher, Hayat" sort="Dagher, Hayat" uniqKey="Dagher H" first="Hayat" last="Dagher">Hayat Dagher</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dalgleish, Raymond" sort="Dalgleish, Raymond" uniqKey="Dalgleish R" first="Raymond" last="Dalgleish">Raymond Dalgleish</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Genetics, University of Leicester, Leicester, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jensen, Shane T" sort="Jensen, Shane T" uniqKey="Jensen S" first="Shane T." last="Jensen">Shane T. Jensen</name><affiliation><nlm:aff id="aff005"><addr-line>Wharton Business School, University of Pennsylvania, Philadelphia, PA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jeunemaitre, Xavier" sort="Jeunemaitre, Xavier" uniqKey="Jeunemaitre X" first="Xavier" last="Jeunemaitre">Xavier Jeunemaitre</name><affiliation><nlm:aff id="aff006"><addr-line>INSERM U970 Paris Cardiovascular Research Centre, Paris France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>University Paris Descartes, Paris Sorbonne Cite, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Savige, Judy" sort="Savige, Judy" uniqKey="Savige J" first="Judy" last="Savige">Judy Savige</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28704418</idno><idno type="pmc">5509119</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509119</idno><idno type="RBID">PMC:5509119</idno><idno type="doi">10.1371/journal.pone.0175582</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002987</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002987</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles</title><author><name sortKey="Parkin, J Des" sort="Parkin, J Des" uniqKey="Parkin J" first="J. Des" last="Parkin">J. Des Parkin</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="San Antonio, James D" sort="San Antonio, James D" uniqKey="San Antonio J" first="James D." last="San Antonio">James D. San Antonio</name><affiliation><nlm:aff id="aff002"><addr-line>Operations, Stryker Global Quality and Operations, Malvern, PA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Persikov, Anton V" sort="Persikov, Anton V" uniqKey="Persikov A" first="Anton V." last="Persikov">Anton V. Persikov</name><affiliation><nlm:aff id="aff003"><addr-line>Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Lab, Princeton, NJ, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dagher, Hayat" sort="Dagher, Hayat" uniqKey="Dagher H" first="Hayat" last="Dagher">Hayat Dagher</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dalgleish, Raymond" sort="Dalgleish, Raymond" uniqKey="Dalgleish R" first="Raymond" last="Dalgleish">Raymond Dalgleish</name><affiliation><nlm:aff id="aff004"><addr-line>Department of Genetics, University of Leicester, Leicester, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jensen, Shane T" sort="Jensen, Shane T" uniqKey="Jensen S" first="Shane T." last="Jensen">Shane T. Jensen</name><affiliation><nlm:aff id="aff005"><addr-line>Wharton Business School, University of Pennsylvania, Philadelphia, PA, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jeunemaitre, Xavier" sort="Jeunemaitre, Xavier" uniqKey="Jeunemaitre X" first="Xavier" last="Jeunemaitre">Xavier Jeunemaitre</name><affiliation><nlm:aff id="aff006"><addr-line>INSERM U970 Paris Cardiovascular Research Centre, Paris France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>University Paris Descartes, Paris Sorbonne Cite, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Savige, Judy" sort="Savige, Judy" uniqKey="Savige J" first="Judy" last="Savige">Judy Savige</name><affiliation><nlm:aff id="aff001"><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Collagen III is critical to the integrity of blood vessels and distensible organs, and in hemostasis. Examination of the human collagen III interactome reveals a nearly identical structural arrangement and charge distribution pattern as for collagen I, with cell interaction domains, fibrillogenesis and enzyme cleavage domains, several major ligand-binding regions, and intermolecular crosslink sites at the same sites. These similarities allow heterotypic fibril formation with, and substitution by, collagen I in embryonic development and wound healing. The collagen III fibril assumes a “flexi-rod” structure with flexible zones interspersed with rod-like domains, which is consistent with the molecule’s prominence in young, pliable tissues and distensible organs. Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2β1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with <italic>COL3A1</italic> disease-causing sequence variants.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ricard Blum, S" uniqKey="Ricard Blum S">S Ricard-Blum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rich, A" uniqKey="Rich A">A Rich</name></author><author><name sortKey="Crick, Fh" uniqKey="Crick F">FH Crick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meek, Km" uniqKey="Meek K">KM Meek</name></author><author><name sortKey="Chapman, Ja" uniqKey="Chapman J">JA Chapman</name></author><author><name sortKey="Hardcastle, Ra" uniqKey="Hardcastle R">RA Hardcastle</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28704418</article-id><article-id pub-id-type="pmc">5509119</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0175582</article-id><article-id pub-id-type="publisher-id">PONE-D-17-00972</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Collagens</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Database and Informatics Methods</subject><subj-group><subject>Bioinformatics</subject><subj-group><subject>Sequence Analysis</subject><subj-group><subject>Sequence Motif Analysis</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Chemical Characterization</subject><subj-group><subject>Binding Analysis</subject><subj-group><subject>Cell Binding Assay</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Extracellular Matrix Proteins</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Chemical Characterization</subject><subj-group><subject>Binding Analysis</subject><subj-group><subject>Receptor-Ligand Binding Assay</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cell Adhesion</subject><subj-group><subject>Integrins</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Structures and Organelles</subject><subj-group><subject>Extracellular Matrix</subject><subj-group><subject>Integrins</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Glycobiology</subject><subj-group><subject>Glycoproteins</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Chemical Characterization</subject><subj-group><subject>Binding Analysis</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>The collαgen III fibril has a “flexi-rod” structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles</article-title><alt-title alt-title-type="running-head">Collagen III interactome reveals structural and functional domain organization</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Parkin</surname><given-names>J. Des</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>San Antonio</surname><given-names>James D.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Persikov</surname><given-names>Anton V.</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dagher</surname><given-names>Hayat</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dalgleish</surname><given-names>Raymond</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jensen</surname><given-names>Shane T.</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jeunemaitre</surname><given-names>Xavier</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-6813-0288</contrib-id><name><surname>Savige</surname><given-names>Judy</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>From the University of Melbourne Department of Medicine (Northern Health), Melbourne, VIC, Australia</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Operations, Stryker Global Quality and Operations, Malvern, PA, United States of America</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Lewis-Sigler Institute for Integrative Genomics, Princeton University, Carl Icahn Lab, Princeton, NJ, United States of America</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Department of Genetics, University of Leicester, Leicester, United Kingdom</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Wharton Business School, University of Pennsylvania, Philadelphia, PA, United States of America</addr-line></aff><aff id="aff006"><label>6</label><addr-line>INSERM U970 Paris Cardiovascular Research Centre, Paris France</addr-line></aff><aff id="aff007"><label>7</label><addr-line>University Paris Descartes, Paris Sorbonne Cite, Paris, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Zheng</surname><given-names>Jie</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Akron, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The employment of JSA in private industry (Stryker, Inc.) does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.</p></fn><fn fn-type="con"><p><list list-type="simple"><list-item><p><bold>Conceptualization:</bold> JDP JDS JAS.</p></list-item><list-item><p><bold>Data curation:</bold> JDP JDS AP HD RD STJ XJ JS.</p></list-item><list-item><p><bold>Formal analysis:</bold> JDP JDS AP STJ JS.</p></list-item><list-item><p><bold>Investigation:</bold> JDP JDS AP STJ JS.</p></list-item><list-item><p><bold>Methodology:</bold> JDP JDS AP STJ JS.</p></list-item><list-item><p><bold>Project administration:</bold> JDP JDS AP HD RD STJ XJ JS.</p></list-item><list-item><p><bold>Resources:</bold> JDP JDS AP RD STJ XJ JS.</p></list-item><list-item><p><bold>Software:</bold> STJ RD.</p></list-item><list-item><p><bold>Supervision:</bold> JDS JS.</p></list-item><list-item><p><bold>Validation:</bold> JDS JS JDP.</p></list-item><list-item><p><bold>Visualization:</bold> JDS JS JDP.</p></list-item><list-item><p><bold>Writing – original draft:</bold> JDS JS JDP.</p></list-item><list-item><p><bold>Writing – review & editing:</bold> JDP JDS AP HD RD STJ XJ JS.</p></list-item></list></p></fn><corresp id="cor001">* E-mail: <email>jasavige@unimelb.edu.au</email></corresp></author-notes><pub-date pub-type="epub"><day>13</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>7</issue><elocation-id>e0175582</elocation-id><history><date date-type="received"><day>9</day><month>1</month><year>2017</year></date><date date-type="accepted"><day>20</day><month>3</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Parkin et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Parkin et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0175582.pdf"></self-uri><abstract><p>Collagen III is critical to the integrity of blood vessels and distensible organs, and in hemostasis. Examination of the human collagen III interactome reveals a nearly identical structural arrangement and charge distribution pattern as for collagen I, with cell interaction domains, fibrillogenesis and enzyme cleavage domains, several major ligand-binding regions, and intermolecular crosslink sites at the same sites. These similarities allow heterotypic fibril formation with, and substitution by, collagen I in embryonic development and wound healing. The collagen III fibril assumes a “flexi-rod” structure with flexible zones interspersed with rod-like domains, which is consistent with the molecule’s prominence in young, pliable tissues and distensible organs. Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2β1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with <italic>COL3A1</italic> disease-causing sequence variants.</p></abstract><funding-group><funding-statement>This research did not receive any specific grant from funding agencies in the public, commercial or not-for profit sectors. The second author of this manuscript (JSA) is an employee of private industry, Stryker, Inc. Stryker provided salary support for JSA, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and has no financial or proprietary interest in the research. The specific roles of JSA in this publication are articulated in the “author contributions’ section.</funding-statement></funding-group><counts><fig-count count="5"></fig-count><table-count count="1"></table-count><page-count count="24"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files.</p></notes></front><body><sec sec-type="intro" id="sec001"><title>Introduction</title><p>The collagens are the major proteins of the extracellular matrix. Each molecule is a homo- or heterotrimer of three α chains with G-X-Y repeats. Twenty-eight different collagens have been identified with 46 distinct chains [<xref rid="pone.0175582.ref001" ref-type="bibr">1</xref>], that serve as scaffolds for the attachment of cells and matrix proteins, but are also biologically active.</p><p>Collagen I is the most abundant collagen, and a heterotrimer of two α1(I) and one α2(I) chains [<xref rid="pone.0175582.ref002" ref-type="bibr">2</xref>]. Its fibrils have a characteristic banding pattern on heavy metal staining because of their charged residues [<xref rid="pone.0175582.ref003" ref-type="bibr">3</xref>, <xref rid="pone.0175582.ref004" ref-type="bibr">4</xref>]. The basic repeating structure of the fibril is the D-period, 67 nm long, composed of one region of complete molecular overlap (overlap zone) and one of incomplete overlap (gap zone). Each D-period contains the complete collagen monomer (M) sequence derived from overlapping consecutive elements designated as M 1–5, where M1 is the most N-terminal and M5 the most C-terminal segment of the collagen sequence (<xref ref-type="fig" rid="pone.0175582.g001">Fig 1</xref>).</p><fig id="pone.0175582.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.g001</object-id><label>Fig 1</label><caption><title>Arrangement of five overlapping collagen III α1 chains in the fibril D-period with overlap and gap zone indicated.</title></caption><graphic xlink:href="pone.0175582.g001"></graphic></fig><p>Collagen III is another fibrillar collagen. It can form heterofibrils with collagen type I, and is often replaced by collagen I in embryonic development and wound healing [<xref rid="pone.0175582.ref005" ref-type="bibr">5</xref>]. It is a homotrimer of three identical α1(III) chains, that together with the collagen I α1(I) and α2(I) chains are members of the A clade [<xref rid="pone.0175582.ref006" ref-type="bibr">6</xref>], and whose corresponding genes (<italic>COL3A1</italic>, <italic>COL1A1</italic> and <italic>COL1A2)</italic> have arisen from a common progenitor.</p><p>The three collagen III α1 chains are cross-linked in a staggered array through lysine residues at four sites on each molecule to form microfibrils [<xref rid="pone.0175582.ref007" ref-type="bibr">7</xref>]. These fibrils demonstrate the same periodic banding as seen with collagen I. Fibril size varies with tissue type and developmental stage, but overall, the fibrils are finer than for collagen I and recognized on staining as reticulin [<xref rid="pone.0175582.ref008" ref-type="bibr">8</xref>].</p><p>Collagen III co-localizes with collagen I in many tissues including the vasculature, bowel and skin [<xref rid="pone.0175582.ref009" ref-type="bibr">9</xref>]. It is generally less abundant than collagen I, except in the walls of distensible organs and blood vessels [<xref rid="pone.0175582.ref010" ref-type="bibr">10</xref>], but its fibril cross-links and proteoglycan-rich matrix contribute mechanical strength and distensibility [<xref rid="pone.0175582.ref011" ref-type="bibr">11</xref>]. Collagen III also participates in a variety of biological functions. It has critical roles in cell-binding, hemostasis and angiogenesis [<xref rid="pone.0175582.ref012" ref-type="bibr">12</xref>], tissue remodeling, fetal development [<xref rid="pone.0175582.ref013" ref-type="bibr">13</xref>], and wound healing [<xref rid="pone.0175582.ref014" ref-type="bibr">14</xref>, <xref rid="pone.0175582.ref015" ref-type="bibr">15</xref>]. It is affected by microbial infections, ageing, diabetes, and inherited disease. Disease-causing <italic>COL3A1</italic> variants result predominantly in vascular Ehlers-Danlos syndrome (EDS type IV) (MIM 130050). This affects one in 150,000 individuals, and is autosomal-dominantly inherited [<xref rid="pone.0175582.ref016" ref-type="bibr">16</xref>]. Clinical features include easy bruising, and arterial, intestinal or uterine rupture (15). The atypical form, acrogeria, is characterized by translucent skin and premature aging of the face and peripheries [<xref rid="pone.0175582.ref016" ref-type="bibr">16</xref>,<xref rid="pone.0175582.ref017" ref-type="bibr">17</xref>], but these features are present to some extent in all affected individuals. <italic>COL3A1</italic> variants have also been associated with cerebral aneurysms [<xref rid="pone.0175582.ref018" ref-type="bibr">18</xref>], gastroesophageal reflux disease [<xref rid="pone.0175582.ref019" ref-type="bibr">19</xref>], and pelvic organ prolapse [<xref rid="pone.0175582.ref020" ref-type="bibr">20</xref>].</p><p>Interactomes are protein maps which indicate structural features and the sites of interactions with other molecules. The unique molecular structure of collagens, with their predominantly rigid, triple helical conformation, allows the construction of maps wherein triple helical domains can be represented as 2D linear arrays of three polypeptide chains. The collagen I interactome has been used to deduce functional and disease-associated domains from ligand-binding data [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>,<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0175582.ref023" ref-type="bibr">23</xref>]. Here we have constructed and analyzed the collagen III interactome. Note that databases exist which archive disease variants mapping to the collagens (<ext-link ext-link-type="uri" xlink:href="http://www.le.ac.uk/genetics/collagen/">http://www.le.ac.uk/genetics/collagen/</ext-link>), or through which researchers can access and plot data of interest onto maps of fibrillar collagens, including collagen III [<xref rid="pone.0175582.ref024" ref-type="bibr">24</xref>]. However, to date a comprehensive analysis of all known ligand binding sites and disease variants for collagen III has not been reported.</p></sec><sec sec-type="results" id="sec002"><title>Results</title><p>The amino acid numbering systems for procollagen III and the mature collagen III protein that are used here are shown in <xref ref-type="supplementary-material" rid="pone.0175582.s001">S1 Table</xref>.</p><sec id="sec003"><title>D-period and banding pattern</title><p>When the cross-linking K residues in the collagen α1(III) chain were aligned with those in the collagen α1(I) and α2(I) chains, collagen III had a nearly identical D-period arrangement to collagen I (Figs <xref ref-type="fig" rid="pone.0175582.g001">1</xref> and <xref ref-type="fig" rid="pone.0175582.g002">2</xref>), with the major crosslink pairs being separated by 843 residues in both collagen types [<xref rid="pone.0175582.ref007" ref-type="bibr">7</xref>,<xref rid="pone.0175582.ref025" ref-type="bibr">25</xref>].</p><fig id="pone.0175582.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.g002</object-id><label>Fig 2</label><caption><title>Arrangement of collagen I α1 (top), α2 (middle) and collagen III α1 (bottom) chains demonstrates approximate alignment of charge across all three molecules in the D-period.</title></caption><graphic xlink:href="pone.0175582.g002"></graphic></fig><p>When the D-periods of the α1(III) chain were examined for positive- (R, K) and negatively- charged (E, D) residues, the charge, although not necessarily the residue type, was typically in register across the D-period, and also with the α1(I) and α2(I) chains, and hence with the collagen I D-period (<xref ref-type="fig" rid="pone.0175582.g002">Fig 2</xref>). The charge was not however symmetrical about the molecules’ midpoints which implies unidirectional alignment of collagen III and I during their assembly into heterotypic fibrils. Charge alignment meant that binding motifs for some ligands, such as proteoglycans and HSP47, are also in the same locations for both collagens.</p></sec><sec id="sec004"><title>Analysis of fibril stability and structure</title><p>Collagen III has a higher G, and lower P content than the other fibrillar collagens [<xref rid="pone.0175582.ref026" ref-type="bibr">26</xref>], and nearly twice the number of atypical triplets as type I collagen (<xref ref-type="fig" rid="pone.0175582.g003">Fig 3</xref>). GPP-rich regions promote triple-helical rigidity with more compact 7/2 symmetry, while non-P (‘atypical’) residues alter the triple helical twist [<xref rid="pone.0175582.ref027" ref-type="bibr">27</xref>]. Thermodynamic studies on collagen peptides show that the GPP triplets are the major contributors to triple-helix stability, and that atypical triplets are destabilizing [<xref rid="pone.0175582.ref028" ref-type="bibr">28</xref>,<xref rid="pone.0175582.ref029" ref-type="bibr">29</xref>]. Atypical and GPP triplets tended to predominate in different bins of the collagen III molecule (<xref ref-type="fig" rid="pone.0175582.g003">Fig 3</xref>). While atypical triplets occurred more often in bins 1, 6, 7, and 9, GPP triplets were more common in bins 2, 3, 4, 8, and 10. There was a strong inverse correlation between atypical and GPP triplets with a Pearson correlation coefficient of -0.52. This suggested the presence of alternating rigid and flexible regions within the D-period, along the length of the collagen III molecule.</p><fig id="pone.0175582.g003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.g003</object-id><label>Fig 3</label><caption><p>a. Collagen III D-period demonstrating location of GPP residues (in red) proposed to confer stability and atypical triplets (GAA, GGP, etc, in other colors) proposed to contribute flexibility.; b. Each monomer of the collagen III D-period was divided into ten bins of equal size (about 23 residues) starting at the N-terminus. The number of GPP triplets and atypical triplets (GAA, GGP, etc) were added for all five monomers and plotted against bin number; c. Relative triple helix stability for amino acid sequences of each monomer within the collagen III D-period was predicted using the collagen stability calculator (<ext-link ext-link-type="uri" xlink:href="http://semimajor.net/collagen_calculator/">http://semimajor.net/collagen_calculator/</ext-link>). Monomers 1–5 represent five segments of the collagen III sequence, beginning at the N-terminus. Three comprise approximately 234 amino acid residues but the two that included the gap zone were shorter. Examining these stability curves together suggests that some regions of the D-period are more stable, and others less so, suggesting a “flexi-rod” model for collagen III; d.Top: Schematic of type III collagen monomer with sites for cell interactions and remodeling flanked by crosslinks (X) and hemostasis domain (H). Bottom: Stability modeling indicates clusters of atypical collagen sequences of lower stability (springs) are interspersed with rigid zones (rods) hosting sequences that carry out crucial biologic functions.</p></caption><graphic xlink:href="pone.0175582.g003"></graphic></fig><p>The collagen stability calculator demonstrated co-localization of local stability variations (<xref ref-type="fig" rid="pone.0175582.g003">Fig 3</xref>), with three major regions of decreased stability, including triplets 5–15, 30–40, and 50–60. We thus propose collagen III functions as a “flexi-rod” in which a confluence of atypical triplets creates flexible domains, allowing focal expansion or of several discrete fibril regions (<xref ref-type="fig" rid="pone.0175582.g003">Fig 3</xref>). Yet, two of the three flexible domains incorporated hydroxyl (OH)-K substrates for intermolecular crosslinking between triple helices. Thus the degree of flexibility of the collagen III fibril afforded by the confluence of atypical amino acid triplets may be modulated by the fibril’s extent of crosslinking and may vary, from highly flexible in young organisms or early in wound healing, to less flexible with the more highly cross-linked protein with ageing or later in scar formation. One of the flexible zones lacked the potential for intermolecular crosslink formation and fell in the middle of the gap zone, a thinner, more pliable fibril region. This suggested that the flexi-rod structure of collagen III, regardless of crosslinking, still confers some flexibility to the polymer.</p><p>The rod-like domains containing the major cell- and ligand- binding sites were located between the relatively flexible zones on collagen III (<xref ref-type="fig" rid="pone.0175582.g003">Fig 3</xref>). This may allow the molecule to preserve the triple helical conformations of the regions critical for biologic function.</p><p>A stability analysis of the type I collagen fibril also revealed a “flexi-rod” structure (data not shown). However, the more abundant atypical triplets in collagen III are consistent with a more flexible polymer, and with collagen III’s predominance in pliable tissues such as the skin of young animals, wounds, and in distensible organs.</p></sec><sec id="sec005"><title>Sites related to structure, assembly, turnover, modification, cleavage and ligand-binding</title><p>These include N- and C-propeptides, A-rich sequences, F residues, C cross-links, K cross-links, O and N glycosylation sites, P glycosylation sites, and cleavage sites (N and C propeptidases, matrix metalloproteinases (MMP), serine proteases, chaperones, Secreted Protein Acidic and Rich in Cysteine (SPARC), and Discoidin domain receptors (DDR1 and DDR2) (<xref ref-type="fig" rid="pone.0175582.g004">Fig 4</xref>).</p><fig id="pone.0175582.g004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.g004</object-id><label>Fig 4</label><caption><title>Human collagen III interactome demonstrating the positions of putative Cell interaction domain, Fibrillogenesis and enzyme cleavage domain, Major ligand-binding regions (MLBR1, 2 and 3), Hemostasis domains, and miscellaneous ligand binding sites and structural features on the collagen triple helix in the fibril’s D-period.</title><p>Sequences or residues comprising binding sites or structural features are indicated by labels that appear beneath the relevant sequence or residue(s) and approximate their spans. Some enzyme cleavage sites are indicated by arrows pointed to the approximate center of the enzyme’s recognition sequence. Abbreviations used in the interactome for the first time include: ang, angiogenesis; AR, A-rich; coll, collagen; hep, heparin/heparan sulfates; FBP, fibronectin-binding protein; and PFR, platelet fibrinogen receptor.</p></caption><graphic xlink:href="pone.0175582.g004"></graphic></fig><sec id="sec006"><title>N- and C-propeptides</title><p>Collagen α1(III) has N- and C-propeptides that are normally cleaved. Retention of the quasi-rigid N-terminal propeptide potentially restricts fiber growth [<xref rid="pone.0175582.ref005" ref-type="bibr">5</xref>,<xref rid="pone.0175582.ref007" ref-type="bibr">7</xref>]. The collagen α1(III) C-propeptide includes the NC1 recognition sequence, <monospace>GNPELPEDVLDVSSR</monospace> [<xref rid="pone.0175582.ref030" ref-type="bibr">30</xref>], critical for triple helix nucleation [<xref rid="pone.0175582.ref031" ref-type="bibr">31</xref>], as well as a HtrA1 serine protease cleavage site [<xref rid="pone.0175582.ref032" ref-type="bibr">32</xref>].</p></sec><sec id="sec007"><title>A-rich sequences</title><p>Collagen III has two A-rich sequences, <monospace>GAAGARGNDGAR</monospace> and <monospace>GPAGERGAPGPAGPRGAA</monospace> that may contribute to elasticity [<xref rid="pone.0175582.ref033" ref-type="bibr">33</xref>]. Similar sequences occur at these locations in collagen I.</p></sec><sec id="sec008"><title>F residues</title><p>Collagen III has three major cross-fibril clusters of F residues in the same locations as in collagens II and III [<xref rid="pone.0175582.ref034" ref-type="bibr">34</xref>] where they are proposed to promote collagen monomer assembly into fibrils. For the collagen III sequence <monospace>RGQPGVMGF</monospace>, F is a crucial component of the DDR2, SPARC and vWF–collagen binding complexes [<xref rid="pone.0175582.ref035" ref-type="bibr">35</xref>,<xref rid="pone.0175582.ref036" ref-type="bibr">36</xref>,<xref rid="pone.0175582.ref037" ref-type="bibr">37</xref>].</p></sec><sec id="sec009"><title>C cross-links</title><p>The C residues at 1196–1197 in the collagen III α1 chains form a disulfide knot [<xref rid="pone.0175582.ref038" ref-type="bibr">38</xref>], that facilitates molecular realignment after denaturation. The mature collagen I protein does not have C residues which selects against trimerization with collagen III. Instead collagen I uses the C-terminal (GPP)<sub>5</sub> motif.</p></sec><sec id="sec010"><title>K cross-links</title><p>Divalent and trivalent crosslinks covalently join collagens III and I [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>]. The K covalent cross-links at residues 110 and 953 stabilize collagen III fibril formation. The other cross-link sites are in the collagen III N- and C-telopeptides [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>].</p></sec><sec id="sec011"><title>O- and N-glycosylation sites</title><p>Collagen III has one O-glycosylation site [<xref rid="pone.0175582.ref039" ref-type="bibr">39</xref>], and N-glycosylation sites at the GXN motifs.</p></sec><sec id="sec012"><title>P hydroxylation sites</title><p>Most P residues in the Yaa position of the GXY triplet in collagen III are 4-hydroxylated. The <monospace>GHPGPIGPPGPR</monospace> motif that is 3-hydroxylated in collagen I and II is not hydroxylated in collagen III [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>]. The absence of this cross-link may contribute to collagen III’s inability to form homotypic fibrils [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>].</p></sec><sec id="sec013"><title>N and C propeptidases</title><p>Meprin a/b cleaves both the N and C-propeptides [<xref rid="pone.0175582.ref040" ref-type="bibr">40</xref>] of collagen III. The N-propeptide is also removed by ADAMTS-2, and the C-propeptide by procollagen C-proteinase, also known as bone morphogenetic protein 1 (BMP1) [<xref rid="pone.0175582.ref040" ref-type="bibr">40</xref>].</p></sec><sec id="sec014"><title>MMP</title><p>MMPs are important in extracellular matrix degradation and tissue remodeling, and activating other MMPs. Collagen III is cleaved by MMPs 1, 2, 3, 9 and 13 at residues 791–806, located about three quarters of the length of the molecule, near the fibrils gap zone [<xref rid="pone.0175582.ref041" ref-type="bibr">41</xref>,<xref rid="pone.0175582.ref042" ref-type="bibr">42</xref>]. There are also cleavage sites nearby for elastase, trypsin and thermolysin thought to act on the soluble, denatured protein [<xref rid="pone.0175582.ref043" ref-type="bibr">43</xref>].</p></sec><sec id="sec015"><title>Serine proteases and other enzymes</title><p>Collagen III α1 chains have consensus sequences for thrombin and factor Xa cleavage, which are potentially important for collagen III’s hemostatic role but may only be relevant to the denatured molecule [<xref rid="pone.0175582.ref044" ref-type="bibr">44</xref>].</p></sec><sec id="sec016"><title>Chaperones</title><p>HSP47 is a procollagen-specific chaperone that recognizes GXR where the R residue is critical [<xref rid="pone.0175582.ref045" ref-type="bibr">45</xref>]. HSP47 stabilizes the collagen triple helix, clamping the three chains in register. Each collagen III α1 chain binding site may have one or two chaperones bound to it, which prevents lateral aggregation of collagen molecules [<xref rid="pone.0175582.ref045" ref-type="bibr">45</xref>]. Not all of the predicted HSP47 binding sites may be functional.</p></sec><sec id="sec017"><title>SPARC</title><p>SPARC acts as a chaperone but also modulates collagen fibril assembly [<xref rid="pone.0175582.ref046" ref-type="bibr">46</xref>] and tissue remodeling. The minimal binding motif in several collagens is GVMGFO [<xref rid="pone.0175582.ref036" ref-type="bibr">36</xref>,<xref rid="pone.0175582.ref046" ref-type="bibr">46</xref>]. Collagen III and I have a common high affinity SPARC binding site but collagen I has an additional low affinity site [<xref rid="pone.0175582.ref046" ref-type="bibr">46</xref>].</p></sec><sec id="sec018"><title>Discoidin domain receptors (DDR1 and DDR2)</title><p>DDRs are tyrosine kinase receptors that induce the expression of MMPs and BMP, and potentially regulate collagen production and organization. Their main binding site in collagen III includes the GVMGFO motif that also binds SPARC, and contributes to the binding of vWF, overlaps with a conserved F residue, and is in the same location in collagen I [<xref rid="pone.0175582.ref047" ref-type="bibr">47</xref>].</p></sec></sec><sec id="sec019"><title>Isoform (P02461-2)</title><p>Expression of the collagen III isoform lacking C-terminal residues 694–996 (UniProt KB) has not been confirmed <italic>in vivo</italic>. It lacks the final monomer of the D-period, which includes the fibrillogenesis domain and sites for the disulfide knot, cross-links, and some ligands, but retains the K residues required for cross-linking.</p></sec><sec id="sec020"><title>Binding sites for extracellular matrix molecules, integrins, cells and other ligands</title><p>These include the extracellular matrix molecules (proteoglycans, collagens, fibronectin, thrombospondin 4, integrins, RGD motif, leucocyte-associated immunoglobulin-like receptors (LAIR) 1 and 2, OSteoClast-associated Receptor (OSCAR) and other binding motifs.</p><sec id="sec021"><title>Proteoglycans</title><p>The binding motifs for proteoglycans in collagen III are GE/DR/KGE/DXGXXGX [<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>] (<xref ref-type="table" rid="pone.0175582.t001">Table 1</xref>). Binding sites for decoron (the core protein of decorin) and dermatan sulfate proteoglycan overlap with the motif KXGDRGE at the e1-d band junction [<xref rid="pone.0175582.ref049" ref-type="bibr">49</xref>]. These are at the same locations as in collagen I [<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>].</p><table-wrap id="pone.0175582.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.t001</object-id><label>Table 1</label><caption><title>Major structural features and ligand binding sites for collagen III.</title></caption><alternatives><graphic id="pone.0175582.t001g" xlink:href="pone.0175582.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Name</th><th align="left" rowspan="1" colspan="1">Motif</th><th align="center" rowspan="1" colspan="1">Sequence</th><th align="center" rowspan="1" colspan="1">Residues</th><th align="center" rowspan="1" colspan="1">Comments</th><th align="center" rowspan="1" colspan="1">Detection method</th><th align="center" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td align="center" colspan="7" rowspan="1">Structural features</td></tr><tr><td align="left" rowspan="1" colspan="1">C cross-links<break></break></td><td align="center" rowspan="1" colspan="1"><monospace>CC</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>CC</monospace></td><td align="center" rowspan="1" colspan="1">1043–1044</td><td align="center" rowspan="1" colspan="1">Forms bonds between collagen III α1 chains</td><td align="center" rowspan="1" colspan="1">X Ray crystallography</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref038" ref-type="bibr">38</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">K cross-links</td><td align="center" rowspan="1" colspan="1"><monospace>GMXGHR</monospace> (bovine)<break></break><monospace>IAGIGGEXA</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GMKGHRGIKGHR</monospace><break></break><monospace>IAGIGGEKA</monospace></td><td align="center" rowspan="1" colspan="1">108–113951–956<break></break>1052–60</td><td align="center" rowspan="1" colspan="1">Cross links collagen III and collagen I or II</td><td align="center" rowspan="1" colspan="1">Enzyme digestion and sequencing</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref007" ref-type="bibr">7</xref>,<xref rid="pone.0175582.ref099" ref-type="bibr">99</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Modification sites and sites related to assembly, trafficking and turnover</td></tr><tr><td align="left" rowspan="1" colspan="1">4 P-hydroxylation</td><td align="center" rowspan="1" colspan="1"><monospace>G-Xaa-P</monospace></td><td align="center" rowspan="1" colspan="1">N/A</td><td align="center" rowspan="1" colspan="1">Multiple sites</td><td align="center" rowspan="1" colspan="1">Stabilizes collagen triple helix</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref100" ref-type="bibr">100</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">O-linked glycosylation</td><td align="center" rowspan="1" colspan="1"><monospace>PGMKGHRG</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>PGMKGHRG</monospace></td><td align="center" rowspan="1" colspan="1">107–114</td><td align="center" rowspan="1" colspan="1">Regulates cross-link maturation</td><td align="center" rowspan="1" colspan="1">Cyanogen bromide fragments, protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref039" ref-type="bibr">39</xref>, <xref rid="pone.0175582.ref101" ref-type="bibr">101</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">N-linked glycosylation</td><td align="center" rowspan="1" colspan="1"><monospace>NXaaS/T</monospace><break></break></td><td align="center" rowspan="1" colspan="1"><monospace>NGS</monospace><break></break><monospace>NGS</monospace></td><td align="center" rowspan="1" colspan="1">236–238<break></break>884–886</td><td align="center" rowspan="1" colspan="1">Unlikely in native collagen</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">NetNGly 1.0</td></tr><tr><td align="left" rowspan="1" colspan="1">NC1 recognition sequence</td><td align="center" rowspan="1" colspan="1"><monospace>GNPELPEDVLDVSSR</monospace></td><td align="center" rowspan="1" colspan="1">C-terminal propeptide</td><td align="center" rowspan="1" colspan="1">C-terminal to onset of triple helix</td><td align="center" rowspan="1" colspan="1">Highly conserved sequence, critical to triple helix nucleation</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref031" ref-type="bibr">31</xref>]<break></break></td></tr><tr><td align="left" rowspan="1" colspan="1">HSP47</td><td align="center" rowspan="1" colspan="1"><monospace>GXR</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GXR</monospace></td><td align="center" rowspan="1" colspan="1">Multiple sites, in the same locations as collagen I α1 and α2</td><td align="center" rowspan="1" colspan="1">Procollagen-specific<break></break> chaperone that facilitates folding in the ER</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref102" ref-type="bibr">102</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Secreted Protein Acidic and Rich in C (SPARC)</td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFO</monospace><break></break><monospace>GAAGFO</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFO</monospace><break></break><monospace>GAAGFP</monospace></td><td align="center" rowspan="1" colspan="1">423–428<break></break>717–722</td><td align="center" rowspan="1" colspan="1">Matricellular protein with roles in cell differentiation and wound healing</td><td align="center" rowspan="1" colspan="1">Rotary shadowing, cyanogen bromide, synthetic peptides</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref046" ref-type="bibr">46</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Membrin</td><td align="center" rowspan="1" colspan="1"><monospace>MxxE</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>MPGE</monospace></td><td align="center" rowspan="1" colspan="1">574–577</td><td align="center" rowspan="1" colspan="1">Transports proteins within the Golgi</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">Minimotif</td></tr><tr><td align="left" rowspan="1" colspan="1">Glycation sites</td><td align="center" rowspan="1" colspan="1">Select K residues</td><td align="center" rowspan="1" colspan="1"><monospace>K</monospace></td><td align="center" rowspan="1" colspan="1">Undefined</td><td align="center" rowspan="1" colspan="1">Advanced glycation end-products may form at select residues</td><td align="center" rowspan="1" colspan="1">Sites in collagen I α1 (434) and α2 chains (453, 479, 924); cross-fibril glycation zone for type I/III fibrils, blue stripe, <xref ref-type="fig" rid="pone.0175582.g004">Fig 4</xref>.</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref088" ref-type="bibr">88</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Cleavage sites</td></tr><tr><td align="left" rowspan="1" colspan="1">Procollagen III N-proteinase</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>NYSP/QYDS</monospace></td><td align="center" rowspan="1" colspan="1">.…/1-4</td><td align="center" rowspan="1" colspan="1">Cleaves native collagen III</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref103" ref-type="bibr">103</xref>,<xref rid="pone.0175582.ref104" ref-type="bibr">104</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">ADAMTS-2</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>NYSP/QYDS</monospace></td><td align="center" rowspan="1" colspan="1">…./1-4</td><td align="center" rowspan="1" colspan="1">N-propeptidase that cleaves collagens I, II III, probably distinct from procollagen III N-proteinase</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref104" ref-type="bibr">104</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Meprin a/b</td><td align="center" rowspan="1" colspan="1"><monospace>G/DEPMDF</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>NYSP/QYDS</monospace><break></break><monospace>PYYG/DEPM</monospace></td><td align="center" rowspan="1" colspan="1">…./1-4<break></break>1065-1068/…</td><td align="center" rowspan="1" colspan="1">Cleaves both N- and C- propeptides</td><td align="center" rowspan="1" colspan="1">SDS-PAGE</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref040" ref-type="bibr">40</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Bone morphogenetic protein 1 (BMP1; Procollagen C-proteinase, PCP)</td><td align="center" rowspan="1" colspan="1"><monospace>G/DEPMDF</monospace></td><td align="center" rowspan="1" colspan="1">C-propeptide</td><td align="center" rowspan="1" colspan="1">1065-1068/…</td><td align="center" rowspan="1" colspan="1">Cleaves C-propeptide</td><td align="center" rowspan="1" colspan="1">SDS-PAGE</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref040" ref-type="bibr">40</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Metalloproteinase-1 (MMP1, 3 and 9)</td><td align="center" rowspan="1" colspan="1"><monospace>GPLGIAGITGARGLA</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GPLGIAGITGARGLA</monospace></td><td align="center" rowspan="1" colspan="1">792–803</td><td align="center" rowspan="1" colspan="1">Cleaves collagen III ¾ along the molecule; activates other MMPs</td><td align="center" rowspan="1" colspan="1">Agarose gels and sequencing</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref105" ref-type="bibr">105</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">MMP3 (stromelysin 1)</td><td align="center" rowspan="1" colspan="1"><monospace>KNGETGPQGP</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>KNGETGPQGP</monospace></td><td align="center" rowspan="1" colspan="1">457–466</td><td align="center" rowspan="1" colspan="1">Cleaves collagen III ¾ along the molecule; activates other MMPs</td><td align="center" rowspan="1" colspan="1">Agarose gels and sequencing</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref105" ref-type="bibr">105</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">High temperature requirement A 1 (HtrA 1) serine protease</td><td align="center" rowspan="1" colspan="1"><monospace>GPVCFL/C</monospace></td><td align="center" rowspan="1" colspan="1">C-propeptide</td><td align="center" rowspan="1" colspan="1">C-terminal to triple helix</td><td align="center" rowspan="1" colspan="1">Serine protease, binds to C-terminus</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay<break></break></td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref032" ref-type="bibr">32</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Clostridium collagenase</td><td align="center" rowspan="1" colspan="1"><monospace>LGPA</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>LGPA</monospace></td><td align="center" rowspan="1" colspan="1">160–163<break></break>325–328</td><td align="center" rowspan="1" colspan="1">Cleavage</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref083" ref-type="bibr">83</xref>,<xref rid="pone.0175582.ref084" ref-type="bibr">84</xref>,<xref rid="pone.0175582.ref106" ref-type="bibr">106</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Caspase 1</td><td align="center" rowspan="1" colspan="1"><monospace>WTD/SS</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>WTD/SS</monospace> in C- propeptide</td><td align="center" rowspan="1" colspan="1">C-terminal to triple helix</td><td align="center" rowspan="1" colspan="1">Cysteine-aspartic protease that activates proteins by cleavage, digests ECM</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref107" ref-type="bibr">107</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Caspase 3–7</td><td align="center" rowspan="1" colspan="1"><monospace>DGKDG</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>DGKDG</monospace></td><td align="center" rowspan="1" colspan="1">311–315</td><td align="center" rowspan="1" colspan="1">Cysteine-aspartic protease, involved in apoptosis and digests extracellular matrix</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref107" ref-type="bibr">107</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Cathepsin D</td><td align="center" rowspan="1" colspan="1"><monospace>KSGVAGGI</monospace> (bovine)</td><td align="center" rowspan="1" colspan="1"><monospace>KSGVAGGL</monospace></td><td align="center" rowspan="1" colspan="1">8–16</td><td align="center" rowspan="1" colspan="1">Non-specific<break></break> tissue proteinase that</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref108" ref-type="bibr">108</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Caspase 3–7</td><td align="center" rowspan="1" colspan="1"><monospace>DGKDG</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>DGKDG</monospace></td><td align="center" rowspan="1" colspan="1">311–315</td><td align="center" rowspan="1" colspan="1">Cysteine-aspartic protease, involved in apoptosis an ddiegests ECM</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref107" ref-type="bibr">107</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Neutrophil elastase</td><td align="center" rowspan="1" colspan="1"><monospace>I/T</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>IT</monospace></td><td align="center" rowspan="1" colspan="1">799/800 and 800/801</td><td align="center" rowspan="1" colspan="1">Cleaves in MMP enzyme cleavage domain</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref069" ref-type="bibr">69</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Trypsin</td><td align="center" rowspan="1" colspan="1"><monospace>R/G</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>RG</monospace></td><td align="center" rowspan="1" colspan="1">Multiple sites</td><td align="center" rowspan="1" colspan="1">Cleaves in MMP enzyme cleavage domain</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref109" ref-type="bibr">109</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Thermolysin</td><td align="center" rowspan="1" colspan="1"><monospace>G/L</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GL</monospace></td><td align="center" rowspan="1" colspan="1">804/805</td><td align="center" rowspan="1" colspan="1">Cleaves in MMP enzyme cleavage domain</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref110" ref-type="bibr">110</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Thrombin</td><td align="center" rowspan="1" colspan="1"><monospace>AGPR/GAA</monospace><break></break><monospace>AGPR/GSP</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>AGPR/GAA</monospace><break></break><monospace>AGPR/GSP</monospace></td><td align="center" rowspan="1" colspan="1">365/366<break></break>641/642</td><td align="center" rowspan="1" colspan="1">Cleavage</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref044" ref-type="bibr">44</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Factor Xa</td><td align="center" rowspan="1" colspan="1"><monospace>DGR/NG</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>DGR/NG</monospace></td><td align="center" rowspan="1" colspan="1">118/119</td><td align="center" rowspan="1" colspan="1">Cleavage</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref044" ref-type="bibr">44</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Binding sites for extracellular matrix molecules, cells and other ligands</td></tr><tr><td align="left" colspan="7" rowspan="1">Extracellular molecules</td></tr><tr><td align="left" rowspan="1" colspan="1">Collagen I, II</td><td align="center" rowspan="1" colspan="1">N-terminal site unresolved<break></break><monospace>KGHR</monospace><break></break><monospace>KGHR</monospace><break></break><monospace>IAGIGGEXA</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>IAGIGGEKA</monospace><break></break><monospace>GPAGMPGFPGMKGHR</monospace> (C-propeptide)</td><td align="center" rowspan="1" colspan="1">99–119, 1052–1068<break></break></td><td align="center" rowspan="1" colspan="1">Form heterotypic fibrils in tissue-specific manner</td><td align="center" rowspan="1" colspan="1">CNBr fragments and synthetic peptides with Western blots</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Keratan sulfate proteoglycan (KSPG)</td><td align="center" rowspan="1" colspan="1"><monospace>GERGEQGPAGS</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GDKGDTGPPGP</monospace></td><td align="center" rowspan="1" colspan="1">474–484</td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>GDRGDAGPKGA</monospace> on collagen 1</td><td align="center" rowspan="1" colspan="1"><monospace>GDKGEPGGPGA</monospace></td><td align="center" rowspan="1" colspan="1">588–598</td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Dermatan sulfate proteoglycan (DSPG)</td><td align="center" rowspan="1" colspan="1"><monospace>GDKGESGPSGP</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GDKGEGGAPGL</monospace></td><td align="center" rowspan="1" colspan="1">624–634</td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>GDRGEPGGPGP</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GERGETGGPGP</monospace></td><td align="center" rowspan="1" colspan="1">645–655</td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>GDRGETGPAGP</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GDRGENGSPGA</monospace></td><td align="center" rowspan="1" colspan="1">879–889<break></break></td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1"><monospace>GDRGETGPAGP</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GDRGESGPAGP</monospace></td><td align="center" rowspan="1" colspan="1">909–919</td><td align="center" rowspan="1" colspan="1">Proposed to regulate spacing between collagen fibrils</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref048" ref-type="bibr">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Heparin<break></break></td><td align="center" rowspan="1" colspan="1"><monospace>KGHR</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>KGHR</monospace></td><td align="center" rowspan="1" colspan="1">110–113<break></break>953–956</td><td align="center" rowspan="1" colspan="1">Inhibits angiogenesis</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay, endothelial tube formation assays</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref111" ref-type="bibr">111</xref>,<xref rid="pone.0175582.ref112" ref-type="bibr">112</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Pigment Epithelium-derived Factor (PEDF, SERPIN F1)</td><td align="center" rowspan="1" colspan="1"><monospace>MKGHRGFDGRNG</monospace><break></break><monospace>IKGHRGFOGNOG</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>MKGHRGFDGRNG</monospace><break></break><monospace>IKGHRGFPGNPG</monospace></td><td align="center" rowspan="1" colspan="1">109–120<break></break>952–963</td><td align="center" rowspan="1" colspan="1">Complexes with collagen in cornea and vitreous</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref052" ref-type="bibr">52</xref>,<xref rid="pone.0175582.ref113" ref-type="bibr">113</xref>]<break></break></td></tr><tr><td align="left" rowspan="1" colspan="1">Decoron (decorin core protein)<break></break></td><td align="center" rowspan="1" colspan="1"><monospace>KXDGRGE</monospace> on collagen I;<break></break><monospace>AKGDRGE</monospace> on collagen I</td><td align="center" rowspan="1" colspan="1"><monospace>GKGDRGE</monospace><break></break><monospace>KSGDGRE</monospace></td><td align="center" rowspan="1" colspan="1">877–883<break></break>907–914</td><td align="center" rowspan="1" colspan="1">Inferred from sequence, position and site on A clade map</td><td align="center" rowspan="1" colspan="1">Rotary shadowing, X Ray crystallography</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref049" ref-type="bibr">49</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Fibronectin-binding protein</td><td align="center" rowspan="1" colspan="1">Binds about 122 nm from C-terminus of collagen I</td><td align="center" rowspan="1" colspan="1">Undefined binding sequence</td><td align="center" rowspan="1" colspan="1">about 800</td><td align="center" rowspan="1" colspan="1">Links fibronectin and collagen III. Binds near MMP cleavage site and near decorin with which it interacts</td><td align="center" rowspan="1" colspan="1">Rotary shadowing, X Ray crystallography</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref057" ref-type="bibr">57</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Secreted protein Acidic and Rich in Cysteine (SPARC, BM40,<break></break>Osteogenin)</td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFO</monospace><break></break><monospace>GAAGFP</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFO</monospace><break></break><monospace>GAAGFP</monospace><break></break></td><td align="center" rowspan="1" colspan="1">423–428<break></break>717–722</td><td align="center" rowspan="1" colspan="1">Secreted glycoprotein important in mineralization<break></break></td><td align="center" rowspan="1" colspan="1">CNBr fragments, synthetic peptides and rotary shadowing</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref046" ref-type="bibr">46</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Thrombospondin</td><td align="center" rowspan="1" colspan="1">Binds close to both N- and C-termini</td><td align="center" rowspan="1" colspan="1">Undefined binding sequence(s)</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Platelet aggregation and antiangiogenic, mediates cell-cell and cell-ECM binding</td><td align="center" rowspan="1" colspan="1">Rotary shadowing</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref058" ref-type="bibr">58</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Tenascin X</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Binds to collagen III and decorin</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref114" ref-type="bibr">114</xref>,<xref rid="pone.0175582.ref115" ref-type="bibr">115</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Cells</td></tr><tr><td align="left" rowspan="1" colspan="1">Integrin α1β1, α2β1</td><td align="center" rowspan="1" colspan="1"><monospace>GRPGER (GROGER)</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GROGER</monospace></td><td align="center" rowspan="1" colspan="1">84–89</td><td align="center" rowspan="1" colspan="1">High affinity, expressed on platelets</td><td align="center" rowspan="1" colspan="1">Rotary shadowing and synthetic peptides, collagen III toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref060" ref-type="bibr">60</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Integrin α2β1</td><td align="center" rowspan="1" colspan="1"><monospace>GLPGER (GLOGER)</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GLOGER</monospace></td><td align="center" rowspan="1" colspan="1">135–140,<break></break>150–155</td><td align="center" rowspan="1" colspan="1">High affinity</td><td align="center" rowspan="1" colspan="1">Rotary shadowing and synthetic peptides, collagen III toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Integrin α2β1</td><td align="center" rowspan="1" colspan="1"><monospace>GAPGER (GAOGER)</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GAOGER</monospace></td><td align="center" rowspan="1" colspan="1">525–530</td><td align="center" rowspan="1" colspan="1">Low affinity</td><td align="center" rowspan="1" colspan="1">Rotary shadowing and synthetic peptides, collagen III toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Integrin α2β1</td><td align="center" rowspan="1" colspan="1"><monospace>GMPGER (GMOGER)</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GMOGER</monospace></td><td align="center" rowspan="1" colspan="1">573–578</td><td align="center" rowspan="1" colspan="1">High affinity</td><td align="center" rowspan="1" colspan="1">Rotary shadowing and synthetic peptides, collagen III toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Integrin α2β1</td><td align="center" rowspan="1" colspan="1"><monospace>GLSGER</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GLSGER</monospace></td><td align="center" rowspan="1" colspan="1">834–839</td><td align="center" rowspan="1" colspan="1">High affinity</td><td align="center" rowspan="1" colspan="1">Rotary shadowing and synthetic peptides, collagen III toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">RGD</td><td align="center" rowspan="1" colspan="1"><monospace>RGD</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>RGD</monospace></td><td align="center" rowspan="1" colspan="1">938–940</td><td align="center" rowspan="1" colspan="1">Integrin- binding site, not usually relevant in native collagen</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref064" ref-type="bibr">64</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">DDR2 (Discoidin domain receptor -2)</td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFO</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GVMGFP</monospace></td><td align="center" rowspan="1" colspan="1">423–428</td><td align="center" rowspan="1" colspan="1">Cell surface collagen receptor, tyrosine kinase receptor that activates fibroblasts</td><td align="center" rowspan="1" colspan="1">Synthetic peptides</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref116" ref-type="bibr">116</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">LAIR-1 (Leukocyte associated Ig-like<break></break>receptor-1)<break></break></td><td align="center" rowspan="1" colspan="1"><monospace>(GPO)10</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GAPGLRGGAGPPGPEGGKGAAGPPGPP</monospace><break></break><monospace>GEGGPOGVAGPOGGSGPAGPOGPQGVK</monospace><break></break><monospace>GPAGPAGAPGPAGSRGAOGPQGPRGDK</monospace></td><td align="center" rowspan="1" colspan="1">537–563<break></break>681–707<break></break>915–941<break></break></td><td align="center" rowspan="1" colspan="1">Inhibits immune<break></break> responses, found on mononuclear cells and thymocytes</td><td align="center" rowspan="1" colspan="1">Solid phase binding to collagen III and<break></break>(GPO)<sub>10</sub> peptide</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref065" ref-type="bibr">65</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">OSCAR (Osteoclast Associated Receptor)</td><td align="center" rowspan="1" colspan="1"><monospace>GPPGPAGFPGAP</monospace><break></break><monospace>GGPGAAGFPGAR</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GPPGPAGFPGAP</monospace><break></break><monospace>GGPGAAGFPGAR</monospace></td><td align="center" rowspan="1" colspan="1">651–662<break></break>714–725</td><td align="center" rowspan="1" colspan="1">Tyrosine kinase-coupled receptor that costimulates osteoclastogenesis</td><td align="center" rowspan="1" colspan="1">Solid phase binding to synthetic peptides and type II toolkit</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref067" ref-type="bibr">67</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">nCAM1<break></break>(Neural cell adhesion molecule1); ICAM1 (Intercellular adhesion molecule 1)</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">One binding site</td><td align="center" rowspan="1" colspan="1">Membrane glycoprotein but also part of the ECM</td><td align="center" rowspan="1" colspan="1">Solid phase binding assays of ligand to native proteins</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref117" ref-type="bibr">117</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">MAG (Myelin- associated glycoprotein)</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Two binding sites</td><td align="center" rowspan="1" colspan="1">Membrane glycoprotein, but also part of the ECM</td><td align="center" rowspan="1" colspan="1">Solid phase radio-ligand binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref117" ref-type="bibr">117</xref>,<xref rid="pone.0175582.ref118" ref-type="bibr">118</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Hemostasis</td></tr><tr><td align="left" rowspan="1" colspan="1">Von Willebrand Factor (VWF)</td><td align="center" rowspan="1" colspan="1"><monospace>RGQPGVMGF</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>RGQPGVMGF</monospace></td><td align="center" rowspan="1" colspan="1"><break></break>422–430</td><td align="center" rowspan="1" colspan="1">Multimeric glycoprotein, adheres to collagen and platelet surface receptors at high shear rate flow</td><td align="center" rowspan="1" colspan="1">Synthetic triple helical peptides and solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref071" ref-type="bibr">71</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelet fibrinogen receptor (IIb/IIIa)</td><td align="center" rowspan="1" colspan="1"><monospace>PXXXD</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>PAGKD</monospace><break></break></td><td align="center" rowspan="1" colspan="1">72–76</td><td align="center" rowspan="1" colspan="1">Controversial, biological significance unknown</td><td align="center" rowspan="1" colspan="1">Protein sequence</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref076" ref-type="bibr">76</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Glycoprotein VI</td><td align="center" rowspan="1" colspan="1"><monospace>GAOGLRGGAGPOGPEGGKGAAGPOGPO</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GAPGLRGGAGPPGPEGGKGAAGPPGPP</monospace></td><td align="center" rowspan="1" colspan="1">537–563</td><td align="center" rowspan="1" colspan="1">Platelet membrane protein mediating collagen-induced aggregation</td><td align="center" rowspan="1" colspan="1">Platelet and GPVI receptor binding to collagens and triple helical peptides in solid phase assays</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref078" ref-type="bibr">78</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelet-binding octapeptide, kindlin-3</td><td align="center" rowspan="1" colspan="1"><monospace>KOGEOGPK</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>KOGEOGPK</monospace></td><td align="center" rowspan="1" colspan="1">502–509</td><td align="center" rowspan="1" colspan="1">Mediates platelet adhesion independent of GpVI and GpIa/IIa</td><td align="center" rowspan="1" colspan="1">Platelet binding to collagen peptides in solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref079" ref-type="bibr">79</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelet-derived growth factor (PDGF)</td><td align="center" rowspan="1" colspan="1">Motif not known</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">C terminal part of collagen III</td><td align="center" rowspan="1" colspan="1">Binds to a tyrosine kinase receptor to stimulate cell growth</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref119" ref-type="bibr">119</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Proteins of infectious agents</td></tr><tr><td align="left" rowspan="1" colspan="1">Langerin</td><td align="center" rowspan="1" colspan="1"><monospace>ASQNITYHCKNS</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>ASQNITYHCKNS</monospace> in pro-peptide</td><td align="center" rowspan="1" colspan="1">N-terminal to triple helix</td><td align="center" rowspan="1" colspan="1">C-type lectin</td><td align="center" rowspan="1" colspan="1">Mass spectrometry</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref082" ref-type="bibr">82</xref>]<break></break></td></tr><tr><td align="left" rowspan="1" colspan="1">YadA (Yersinia adhesion A)</td><td align="center" rowspan="1" colspan="1"><monospace>GPO</monospace> to <monospace>(GPO)6</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>(GPP)3</monospace></td><td align="center" rowspan="1" colspan="1">24–32</td><td align="center" rowspan="1" colspan="1">Outer membrane<break></break> protein important in adhesion</td><td align="center" rowspan="1" colspan="1">Solid phase binding to synthetic triple-helical<break></break> peptides</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref085" ref-type="bibr">85</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">AAEL010235<break></break>Aegyptin</td><td align="center" rowspan="1" colspan="1"><monospace>RGQPGVMGF</monospace><break></break>(high affinity)<break></break><monospace>(GPO)10,</monospace><break></break><monospace>GFOGER</monospace> (lower affinity)</td><td align="center" rowspan="1" colspan="1"><break></break>Several</td><td align="center" rowspan="1" colspan="1">419–427<break></break></td><td align="center" rowspan="1" colspan="1">Anticoagulant from saliva of blood sucking insect, Aedes aegypti; inhibits binding of vWF, glycoprotein VI and α2β1integrin</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay<break></break></td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref072" ref-type="bibr">72</xref>,<xref rid="pone.0175582.ref073" ref-type="bibr">73</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Calin</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">About<break></break>419–427</td><td align="center" rowspan="1" colspan="1">Anticoagulant in leech saliva (Hirudo medicinalis)</td><td align="center" rowspan="1" colspan="1">Inhibits VWF binding to collagen III</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref074" ref-type="bibr">74</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Leech antiplatelet agent (LAPP)</td><td align="center" rowspan="1" colspan="1">Bovine<break></break><monospace>GPPGPRGGAGPPGPEGGK</monospace></td><td align="center" rowspan="1" colspan="1"><monospace>GAPGLRGGAGPPGPEGGK</monospace></td><td align="center" rowspan="1" colspan="1">537–554</td><td align="center" rowspan="1" colspan="1">Anticoagulant in<break></break> Leech saliva</td><td align="center" rowspan="1" colspan="1">Inhibits VWF binding to collagen III</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref075" ref-type="bibr">75</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">MIP (Macrophage<break></break>infectivity<break></break>potentiator protein)</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Virulence factor found in Legionella</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref086" ref-type="bibr">86</xref>]</td></tr><tr><td align="center" colspan="7" rowspan="1">Miscellaneous ligands</td></tr><tr><td align="left" rowspan="1" colspan="1">G protein-coupled receptor 56 (GPR56)</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Orphan G-protein coupled receptor, important in cortical development</td><td align="center" rowspan="1" colspan="1">Solution phase “pull down” binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref120" ref-type="bibr">120</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">PR47 (47 Kd platelet receptor for collagen III)</td><td align="center" rowspan="1" colspan="1">Motif unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Unknown</td><td align="center" rowspan="1" colspan="1">Membrane receptor for collagen III similar to collagen I receptor</td><td align="center" rowspan="1" colspan="1">Solid phase binding assay</td><td align="center" rowspan="1" colspan="1">[<xref rid="pone.0175582.ref121" ref-type="bibr">121</xref>,<xref rid="pone.0175582.ref122" ref-type="bibr">122</xref>,<xref rid="pone.0175582.ref123" ref-type="bibr">123</xref>]</td></tr></tbody></table></alternatives></table-wrap><p>The heparan sulfate binding motif is KGHRGF in collagen III and there are two sites at the N and C-termini in the same locations as for collagen I. The heparan sulfate proteoglycans act as co-receptors for growth factors and are pro-angiogenic [<xref rid="pone.0175582.ref050" ref-type="bibr">50</xref>].</p><p>Pigment epithelium-derived factor (PEDF), also known as Serpin F1, has a variety of functions including being anti-angiogenic and anti-tumorigenic. It inhibits VEGF expression but upregulates that of thrombospondin [<xref rid="pone.0175582.ref051" ref-type="bibr">51</xref>]. It binds to the same residues in collagen III as heparin and heparan sulfate [<xref rid="pone.0175582.ref052" ref-type="bibr">52</xref>].</p><p>Decoron and probably biglycan bind at two sites in bands d and e in collagens I and III [<xref rid="pone.0175582.ref049" ref-type="bibr">49</xref>, <xref rid="pone.0175582.ref053" ref-type="bibr">53</xref>]. Decorin also binds to fibronectin, complement component C1q, epidermal growth factor receptor (EGFR) and transforming growth factor β (TGFβ). Decorin binding to collagen III inhibits fibrillogenesis, but is pro-angiogenic [<xref rid="pone.0175582.ref049" ref-type="bibr">49</xref>, <xref rid="pone.0175582.ref054" ref-type="bibr">54</xref>].</p></sec><sec id="sec022"><title>Collagens</title><p>Collagen III binds covalently to collagens I and II through cross-links at their N- and C-termini to form heterotypic fibrils [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>], that are thinner than those comprising collagen I alone [<xref rid="pone.0175582.ref055" ref-type="bibr">55</xref>]. Collagen III lacks 3OH-P residues [<xref rid="pone.0175582.ref025" ref-type="bibr">25</xref>] which may impair its ability to extend laterally and determines its peripheral location in the fibril [<xref rid="pone.0175582.ref055" ref-type="bibr">55</xref>,<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>]. Notably, the collagen III triple helix is fifteen residues longer than that of collagen I or II but it is not known how this feature may affect the assembly, structure or function of heterotypic fibrils. In cartilage, collagen III copolymerizes via a trivalent cross-link with collagen II [<xref rid="pone.0175582.ref056" ref-type="bibr">56</xref>] through the same sites [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>]. Collagen V often occurs together with collagen III but there is no evidence currently for intermolecular crosslinking.</p></sec><sec id="sec023"><title>Fibronectin</title><p>There is no evidence for direct binding of collagen III to fibronectin. However a fibronectin-binding protein interacts with collagen III at about residue 800, after taking into account the propeptide [<xref rid="pone.0175582.ref057" ref-type="bibr">57</xref>], which is the same location that fibronectin binds in collagen I and II. This means that collagen III potentially binds to fibronectin and decorin on the same monomer, near the sites for MMP cleavage and heparan sulfate binding. The proximity to the fibrillogenesis domain suggests a regulatory role of fibronectin in collagen III chain assembly and degradation [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>], and in particular, MMP cleavage potentially separates the fibronectin- and decorin- binding sites.</p></sec><sec id="sec024"><title>Thrombospondin 4</title><p>Thrombospondin is found in extracellular matrix, but also in platelets, and it contributes to platelet aggregation and inhibits angiogenesis. Thrombospondin binds to the N- and C-termini of collagen III [<xref rid="pone.0175582.ref058" ref-type="bibr">58</xref>,<xref rid="pone.0175582.ref059" ref-type="bibr">59</xref>].</p></sec><sec id="sec025"><title>Integrins</title><p>Collagen III binds to the α1β1 and α2β1 integrins, and potentially a variety of cells. Most P residues in the collagen III α1 chain are hydroxylated, which enhances integrin binding. The collagen III α1 chain has three integrin binding sites including GRPGER [<xref rid="pone.0175582.ref060" ref-type="bibr">60</xref>], GLPGEN, a high affinity site for α1β1 [<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>], and GMPGER, of rather lower affinity for α2β1 than GRPGERV [<xref rid="pone.0175582.ref062" ref-type="bibr">62</xref>]. Two lower affinity sites, GAPGER [<xref rid="pone.0175582.ref060" ref-type="bibr">60</xref>,<xref rid="pone.0175582.ref063" ref-type="bibr">63</xref>] and GLSGER have also been described. The GAPGER motif at residues 525–530 in the cell interaction domain [<xref rid="pone.0175582.ref060" ref-type="bibr">60</xref>], is at the same location as the collagen I high affinity site, GFPGER.</p><p>The RGD archetypal integrin- binding motif is thought to be less important in collagen where the triple helical conformation renders it inaccessible [<xref rid="pone.0175582.ref064" ref-type="bibr">64</xref>]. However the single RGD site in collagen III is in the same location as in collagen I, and may be exposed after enzymatic cleavage and thus become available for ligation by some integrin receptors [<xref rid="pone.0175582.ref064" ref-type="bibr">64</xref>].</p></sec><sec id="sec026"><title>LAIR 1 and 2</title><p>LAIR-1 is an immune regulatory receptor expressed on mononuclear cells [<xref rid="pone.0175582.ref065" ref-type="bibr">65</xref>]. LAIR-2 blocks the binding of LAIR-1 to collagen III [<xref rid="pone.0175582.ref066" ref-type="bibr">66</xref>]. Both LAIR-1 and -2 bind to (GPO)<sub>3</sub>, and there are at least two sites for interaction on collagen III.</p></sec><sec id="sec027"><title>OSCAR</title><p>This co-stimulates monocytes through the Fc receptor and activates osteoclast formation, resulting in bone resorption. OSCAR binds to <monospace>GPOGPAGFOGAO</monospace> with <monospace>GPOGPXGFX</monospace> as the minimum motif, where P can be substituted by A [<xref rid="pone.0175582.ref067" ref-type="bibr">67</xref>]. This sequence overlaps with a dermatan sulfate binding site. There is a second possible OSCAR binding site, <monospace>GGPGAAGFPGAR</monospace>.</p></sec><sec id="sec028"><title>Other cell-binding motifs</title><p>Collagen III also binds to ICAM1 on endothelial and immune cells, and NCAM1 on neurons, glia, skeletal muscle and natural killer cells but the binding motifs are unknown.</p></sec></sec><sec id="sec029"><title>Major structural domains</title><p>These include the major ligand-binding regions 1, 2 and 3 (MLBR1, 2 and 3), a cell-interaction domain, a Gap, an MMP/enzyme cleavage domain and the fibrillogenesis domain.</p><sec id="sec030"><title>MLBR 1, 2 and 3</title><p>MLBR1 is found in approximately the same locations in collagen III and collagen I, and both sites share many binding motifs and ligands. Both MLBR1 have motifs for integrin-binding, intermolecular crosslinking, angiogenesis, and heparin-binding.</p><p>However, MLBR2 on collagen III includes the hemostasis- binding sites on Monomer 2, and MLBR3 includes the cell interaction domain and several neighboring functional domains on Monomer 3. This contrasts with collagen I where MLBR2 (with the greatest number of ligand binding sites) is located on Monomer 4 and MLBR3 on Monomer 5.</p><p>Notably, only collagen I has binding sites for the ligands involved in mineralization: cartilage oligomeric matrix protein (COMP or thrombospondin 5) and phosphophoryn. Where collagen III is increased in diseased bone or dentin, the tissues are looser, less-mineralized, and heal poorly after fractures [<xref rid="pone.0175582.ref068" ref-type="bibr">68</xref>].</p></sec><sec id="sec031"><title>Cell interaction domain</title><p>The cell interaction domain of collagen III is relatively exposed and allows access to cell surface integrins [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>,<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>], e.g., α2β1 integrin ligation of GAPGER [<xref rid="pone.0175582.ref061" ref-type="bibr">61</xref>], as well as sites for platelets and LAIR-collagen ligation (8,9). Collagen I has an α1β1/α2β1 integrin binding site, GFPGER, at this location.</p></sec><sec id="sec032"><title>Gap</title><p>The gap zone of collagen III is near the MMP/enzyme cleavage domain, and access to binding sites and functional domains therein may be prevented or modulated to a great extent by collagen III’s C-terminus, whereas its removal could allow access.</p></sec><sec id="sec033"><title>MMP/enzyme cleavage domain</title><p>This domain falls near the overlap/gap zone border. Generally, enzyme access to the collagen III fibril is limited except at this location, where a paucity of imino acids is proposed to yield a looser fibril structure to facilitate enzyme access [<xref rid="pone.0175582.ref069" ref-type="bibr">69</xref>].</p></sec><sec id="sec034"><title>Fibrillogenesis domain</title><p>Sites involved in protein folding, fibrillogenesis and fibril stabilization in both collagen III and I include the C-proteinase cleavage motif, disulfide knot, and cross-link sites.</p></sec></sec><sec id="sec035"><title>Functional and disease-associated sites</title><p>The interactome had sites that reflected the normal biological functions of collagen III (hemostasis, angiogenesis, cell-binding) and that were associated with disease (infection, ageing and diabetes, and genetic variants).</p><sec id="sec036"><title>Hemostasis regulatory domains</title><p>The Hemostasis domain 1 is located on M2 in band d, and binds von Willebrand factor (vWF), and salivary proteins from biting insects.</p><p>vWF mediates platelet adhesion in damaged vessels, and has been implicated in angiogenesis, and cancer spread [<xref rid="pone.0175582.ref070" ref-type="bibr">70</xref>]. It may normally be inaccessible because of proteoglycan binding, but trauma may expose the subendothelial collagen III binding sites. vWF binds to a highly conserved motif (<monospace>RGQPGVMGF</monospace>) in collagen III and I [<xref rid="pone.0175582.ref071" ref-type="bibr">71</xref>]. After circulating platelets attach to collagen III through the vWF binding site, they may then engage the glycoprotein VI and integrin α2β1 sites.</p><p>This domain also contains motifs for the mosquito salivary protein aegyptin [<xref rid="pone.0175582.ref072" ref-type="bibr">72</xref>, <xref rid="pone.0175582.ref073" ref-type="bibr">73</xref>], and salivary products from ticks and leeches (aegyptin, calin and rLAPP) [<xref rid="pone.0175582.ref074" ref-type="bibr">74</xref>]. Some of these anticoagulants bind directly to collagen III, blocking vWF binding [<xref rid="pone.0175582.ref074" ref-type="bibr">74</xref>,<xref rid="pone.0175582.ref075" ref-type="bibr">75</xref>]. Aegyptin from the salivary gland of <italic>Aedes aegypti</italic> mosquito binds to <monospace>RGQPGVMGF</monospace> in collagen III.</p><p>There is a predicted motif (PKGND) similar to the platelet fibrinogen receptor binding site (Glycoprotein IIb/IIIa) (PXXXD) near the vWF binding site and a PAGKD motif near the integrin α2β1 motif [<xref rid="pone.0175582.ref076" ref-type="bibr">76</xref>].</p><p>The Hemostasis domain 2 is located at the cell interaction domain, with binding sites for platelet receptors, glycoprotein VI, Type III collagen binding protein (TIIICBP; kindlin) and integrin α2β1 [<xref rid="pone.0175582.ref075" ref-type="bibr">75</xref>]. Glycoprotein VI and kindlin-3 are involved in platelet glycoprotein IIb/IIIa activation.</p><p>Glycoprotein VI binding may be mediated by (GPO)<sub>4</sub> at the N-terminus of collagen III where P hydroxylation is required for binding [<xref rid="pone.0175582.ref077" ref-type="bibr">77</xref>] but fewer repeats and interrupted sequences, such as <monospace>GPOGPEGGKGAAGPOGPO</monospace>, are also effective [<xref rid="pone.0175582.ref078" ref-type="bibr">78</xref>]. Both sites are recognized by LAIR1.</p><p>Collagen III binding protein (TIIICBP; kindlin-3) may recognize a linear platelet-binding octapeptide (KOGEOGPK), located between the vWF and integrin-binding motifs [<xref rid="pone.0175582.ref079" ref-type="bibr">79</xref>], but its biological relevance is controversial.</p><p>The integrin α2β1 (Gp Ia/IIa) binding site facilitates platelet binding and activation through other receptors, notably Glycoprotein VI.</p></sec><sec id="sec037"><title>Angiogenesis</title><p>Major binding sites involved in angiogenesis are the same for collagen III and collagen I, and include sites for heparin, α2β1 integrin, vWF, fibronectin and decorin [<xref rid="pone.0175582.ref080" ref-type="bibr">80</xref>, <xref rid="pone.0175582.ref081" ref-type="bibr">81</xref>]. All these except for vWF are located at the C-terminus, and are absent from the terminal fragment after MMP cleavage.</p></sec><sec id="sec038"><title>Infection</title><p>Collagen III has binding sites for a number of mainly adhesive proteins produced by infectious organisms. These include langerin, a C-type lectin, which binds to <monospace>ASQNITYHCKNS</monospace>, a motif found in collagen III and I propeptides [<xref rid="pone.0175582.ref082" ref-type="bibr">82</xref>]. Collagen III is also susceptible to cleavage by <italic>Clostridium</italic> collagenase at the LGPA motif [<xref rid="pone.0175582.ref083" ref-type="bibr">83</xref>, <xref rid="pone.0175582.ref084" ref-type="bibr">84</xref>]. <italic>Yersinia</italic> adhesion A (YadA) binds to (GPO)<sub>3</sub> [<xref rid="pone.0175582.ref085" ref-type="bibr">85</xref>] and several other sites, especially those rich in imino acids, or hydrophobic or uncharged residues. Aegyptin, calin and rLAPP, from mosquitoes, ticks and leeches, all bind at different collagen III sites.</p><p>Collagen III also binds to macrophage infectivity potentiator protein (MIP) which is a <italic>Legionella</italic> virulence factor [<xref rid="pone.0175582.ref086" ref-type="bibr">86</xref>]. Its binding site in collagen III site is unknown, and the motif in collagen IV (CPSGWS) is not present in collagen III [<xref rid="pone.0175582.ref087" ref-type="bibr">87</xref>].</p></sec><sec id="sec039"><title>Ageing and diabetes</title><p>Collagens are long-lived proteins, and glycation in diabetes and ageing results in advanced glycation end-products, stiffness and interference with ligand binding [<xref rid="pone.0175582.ref011" ref-type="bibr">11</xref>]. The main glycation sites in collagen I localize to K residues within bands c and d [<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0175582.ref088" ref-type="bibr">88</xref>], which are conserved in collagen III. Glycation at residue 431 potentially interferes with the binding of vWF, SPARC and DDRs.</p></sec><sec id="sec040"><title>Genetic variants</title><p>There were 396 different missense variants in the <italic>COL3A1</italic> variant database affecting residues in the collagen III D-period. There were also three nonsense variants and a two-base deletion all in the terminal exon. This corresponded to a total of 400 variants at 254 unique locations affecting the D-period monomers.</p><p>Ten thousand random variant maps were generated each with 400 variants, randomly distributed throughout the collagen III α1 chain. The highest variant frequency peak was then calculated from each random map, and compared with the highest mutation frequency peak in the observed variant map (22.2). There were more frequent variants in residues 1000–1050 when repeated variants at the same residues were considered (<xref ref-type="fig" rid="pone.0175582.g005">Fig 5</xref>). This was also true for collagen I. None of the 1000 random maps had such a high peak variant frequency, and the observed variant peak was very significant, with a p value of < 0.0001. This increase was not significant when only unique locations were considered.</p><fig id="pone.0175582.g005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0175582.g005</object-id><label>Fig 5</label><caption><title>Missense mutation distribution in collagen III.</title><p>Missense mutation frequency along the residues of the collagen III chain. This demonstrates the non-random distribution of variation.</p></caption><graphic xlink:href="pone.0175582.g005"></graphic></fig><p>There were also fewer variants in the C-propeptide residues 1068 to 1315 compared with the randomly–generated variant maps (p<0.0001). None of the other 10,000 randomly-generated maps had a 250 residue window with 16 or fewer variants. There are fewer sequence variants in the C-propeptides than expected by chance (p<0.0001). This is also true for collagen I. The collagen III C-propeptide is critical in chain aggregation prior to triple-helix formation. Two chain-recognition sequences of 12 and 3 amino acids ensure that only procollagen III participates in triple helix formation. The sequences contribute to a complex three-dimensional structure comprising helices, β-strands and turns [<xref rid="pone.0175582.ref030" ref-type="bibr">30</xref>]. The C-propeptide includes a single N-linked glycosylation site, eight conserved C residues essential for the inter-chain disulfide bonds, and six residues for Ca<sup>2+</sup> binding. Together, these represent 157 of the 245 C-propeptide residues. Counterintuitively, most of the few disease-causing variants in the C-propeptide do not affect residues in identifiable structural or functional motifs (<xref ref-type="supplementary-material" rid="pone.0175582.s002">S2 Table</xref>). However, amino acid substitutions, for example, at propeptide positions 92, 211 or 219, might disrupt the three-dimensional structure [<xref rid="pone.0175582.ref089" ref-type="bibr">89</xref>] but their pathogenicity is still unproven. Thus, substitutions at some residues in the C-propeptide may result in EDS, some in perinatal lethality, and others in a minimal or undetectable phenotype.</p><p>For both collagen III and I, the increased numbers of missense variants in the Cell interaction domain and C-terminus were congruent [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>,<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>], but there was no obvious correlation between the apparently non-random distributions of variants and functionally important sites.</p><p>This study examined the effect of variant location, rather than variant type, on clinical phenotype. Already <italic>COL3A1</italic> variant type (G substitutions, splice site mutations, indels) are known to affect disease severity, being associated with an earlier age at onset of the first major complication [<xref rid="pone.0175582.ref090" ref-type="bibr">90</xref>].</p><p>Bruising is common with <italic>COL3A1</italic> missense variants, but massive hemorrhage is rare except with viscus rupture with vascular EDS, despite the two hemostasis domains found in collagen III. Collagen I also has a site for vWF, but binding is low affinity and bleeding does not occur with <italic>COL1A1</italic> variants.</p><p>Some <italic>COL3A1</italic> variants are associated with particular clinical phenotypes. <italic>COL3A1</italic> missense variants in residues 652–925 have been reported more often with acrogeria [<xref rid="pone.0175582.ref091" ref-type="bibr">91</xref>]. The p.A698T [<xref rid="pone.0175582.ref018" ref-type="bibr">18</xref>,<xref rid="pone.0175582.ref020" ref-type="bibr">20</xref>] near the glycoprotein VI binding motif and the cell interaction domain has been associated with bleeding cerebral aneurysms or pelvic organ prolapse [<xref rid="pone.0175582.ref092" ref-type="bibr">92</xref>]. Gastroesophageal reflux and hiatus hernia may both be linked to <italic>COL3A1</italic> [<xref rid="pone.0175582.ref019" ref-type="bibr">19</xref>] although no allele has yet been identified.</p><p>Other mutant genes that produce a vascular EDS-like phenotype often encode binding partners of collagen III. These include the collagen I α1 and α2 chains, collagen V α1 and α2 chains, tenascin X, lysyl hydroxylase and ADAMTS2.</p></sec></sec></sec><sec sec-type="conclusions" id="sec041"><title>Discussion</title><p>The collagen III interactome demonstrates an almost identical arrangement of structural and functional domains as collagen I. Both D-periods have the same number and spacing of intermolecular crosslink sites, and the location of charged residues, and hence fibril banding, is largely congruent. In addition, many of the major structural and functional domains (cell interaction domains, fibrillogenesis and enzyme cleavage sites, and major ligand-binding regions) were found in the same locations. These similarities enable collagen III and I to assemble in register to produce heterofibrils and carry out common biologic functions. They also enable collagen III to be replaced by collagen I in embryogenesis and wound healing. Yet, a major difference between collagen I and III identified here relates to the potential for greater flexibility of collagen III, which makes it an ideal structural component of embryonic tissues, early wound healing, and distensible organs in the adult (vasculature, uterus, small bowel).</p><p>In some tissues the retention of the N-propeptide by collagen III is consistent with its inability to extend laterally, and its fibrils being smaller and more peripherally located in the heterotypic fibril than those of collagen I.</p><p>Clusters of disease-causing missense variants that may reflect residues necessary for molecular folding, fibril assembly, or ligand interactions, as well as variant-free regions map to the same locations in both collagens III and I [<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>]. Yet, the clinical phenotypes associated with variants in the collagen III and I genes are very different. Osteogenesis imperfecta is characterized by bone fragility, and vascular EDS by distensible organ rupture, acrogeria and bleeding. This suggests different tissue expression patterns and binding partners. Thus, for example, collagen I binds to proteins that are required for biomineralization, with the overlap zone of collagen I incorporating binding sites for COMP and phosphophoryn that are not present in collagen III.</p><p>The organ rupture seen in vascular EDS may result from increased collagen III in large arteries and hollow organs rather than altered elastic properties since collagen III does not bind to elastin [<xref rid="pone.0175582.ref016" ref-type="bibr">16</xref>]. The clinical features of acrogeria probably relate to reduced collagen III in subcutaneous tissues [<xref rid="pone.0175582.ref093" ref-type="bibr">93</xref>]. An association with uterine prolapse, hiatus hernia and gastroesophageal reflux, if substantiated, may reflect less abundant collagen III and increased tissue laxity [<xref rid="pone.0175582.ref019" ref-type="bibr">19</xref>,<xref rid="pone.0175582.ref020" ref-type="bibr">20</xref>]. Cumulative ‘wear- and- tear’ in an organ structurally dependent on collagen III may contribute to rupture in adult life.</p><p>Although both collagens III and I bind vWF, only <italic>COL3A1</italic> variants commonly produce bleeding. This is probably because collagen III has more hemostatic ligand binding sites and a higher affinity for vWF [<xref rid="pone.0175582.ref071" ref-type="bibr">71</xref>], and is more abundant in the vascular sub-endothelium and more accessible on the outer fibril surface. The collagen III α1 chain has several closely- related binding motifs for platelet proteins that are critical in platelet immobilization and located in the Cell interaction domain. These sites have not been demonstrated in type I collagen. In addition, the collagen III α1 hemostasis domain is about 100 residues from the vWF binding motif, and platelets bound to the Cell interaction domain may bind simultaneously to the large vWF multimer.</p><p>In conclusion, interactomes summarize our understanding of a molecule’s structure and function, suggest further interactions and roles, and help explain how missense variants produce clinical phenotypes. The collagen III interactome emphasizes its resemblance to collagen I, indicates how its architecture confers flexibility, and explains its role in hemostasis. These results may also have practical applications in the design of bioactive yet flexible extracellular matrix scaffolds for a variety of uses in medical devices.</p></sec><sec sec-type="materials|methods" id="sec042"><title>Experimental procedures</title><sec id="sec043"><title>Construction of the collagen III interactome</title><p>We constructed the interactome of a collagen type III D-period, examined its structural features, charge distribution, ligand-binding sites, and missense sequence variant distribution, and compared these features with those for collagen I.</p><p>The reference sequences for the human pro-collagen α 1(III) (UniProt P02461) and collagen α1(I) and α2(I) chains (UniProt P02452 and P08123 respectively) were used.</p><p>The collagen α1(III) chain is 1466 amino acids, with a signal peptide (23 aa), N-terminal propeptide (130 aa), collagenous sequence (1068 aa), and C-terminal propeptide (245 aa). Here we renumbered the amino acid from one D-period as 1 to 1068, with N- and C-telopeptides (14 and 25 aa respectively) and a triple helix (1029 aa) [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>] corresponding to amino acids 154 to 1221 in the reference sequence. Numbers from the interactome [Reference sequence number -153], were used to describe variants so that numbering began at the start of the mature protein.</p></sec><sec id="sec044"><title>Alignment of charge residues in collagen III and collagen I interactomes</title><p>The cross-link K residues in the collagen α1(III) chain were aligned with those in the collagen α1(I) and α2(I) chains, and the D-periods examined for positively- (R, K) and negatively- charged (E, D) residues.</p></sec><sec id="sec045"><title>Analysis of fibril stability and structure</title><p>The distribution of atypical amino acid triplets, that confer flexibility such as GAA or GGY, and of GPP-rich regions that promote rigidity, was examined for randomness. The relationship of atypical and GPP triplets was then examined in the overlapping D-period regions. The numbers of atypical and GPP triplets were counted in ten ‘bins’ of equal size, starting from the N-terminus, summed over the D-period and compared.</p><p>The location of regions of high and low-stability within the collagen III D-period were examined using the Collagen Stability Calculator <ext-link ext-link-type="uri" xlink:href="http://compbio.cs.princeton.edu/csc/">http://compbio.cs.princeton.edu/csc/</ext-link>[<xref rid="pone.0175582.ref094" ref-type="bibr">94</xref>].</p></sec><sec id="sec046"><title>Sites related to structure, assembly, turnover, modification, cleavage and ligand-binding</title><p>Binding sites and structural motifs described for collagen III were identified using the search terms ‘collagen III’, ‘ligand’, ‘binding partner’ etc, from the scientific literature, open access web sites (UniProt, UCSC, Biogrid, Reactome, STRING, MINT, IntAct, and Ex-PASy Peptide Cutter, see later for websites), and the collagen I interactomes (,) [<xref rid="pone.0175582.ref021" ref-type="bibr">21</xref>,<xref rid="pone.0175582.ref022" ref-type="bibr">22</xref>].</p><p>In general, previously-reported ligand-binding sites were derived from experiments using the native collagen III molecule, triple helical mimetic peptides or fragments thereof, or from measurements based on rotary shadowing electron microscopy of type III collagen-ligand complexes assuming that type III collagen residues were spaced an average of 0.286 nm apart [<xref rid="pone.0175582.ref095" ref-type="bibr">95</xref>]. Binding sites on fragments and peptides derived from type III collagen were included because, <italic>in vivo</italic>, some ligands bind only to the denatured collagen.</p><p>The collagen III reference sequence was also examined for short motifs with biological functions described in other proteins (ELM, MnM databases).</p></sec><sec id="sec047"><title>Functional and disease-associated sites</title><p>The map was examined for sites that reflected the normal biological functions of collagen III (hemostasis, angiogenesis, cell-binding, etc) and disease associations (infection, glycation, inherited disease).</p><p>Non-synonymous DNA missense variants were identified from a search of the open access <italic>COL3A1</italic> web databases (<ext-link ext-link-type="uri" xlink:href="http://eds.gene.le.ac.uk/home.php?select_db=COL3A1">http://eds.gene.le.ac.uk/home.php?select_db=COL3A1</ext-link>) on 6 July 2016). The locations of missense variants was examined for randomness. A Gaussian kernel smoother was used to calculate a smoothed variant frequency at each residue in the coding sequence corresponding to the D-period [<xref rid="pone.0175582.ref096" ref-type="bibr">96</xref>]. Ten thousand random variant maps were generated using the number of unique variant locations in the protein sequence. The peaks found using the data from the <italic>COL3A1</italic> variant database distribution were compared with proportion of maps with a randomly-generated variant peak of this magnitude [<xref rid="pone.0175582.ref097" ref-type="bibr">97</xref>]. A similar randomization analysis was performed to examine the lack of variants in any region. These analyses were performed using the statistical software R [<xref rid="pone.0175582.ref098" ref-type="bibr">98</xref>].</p></sec></sec><sec sec-type="supplementary-material" id="sec048"><title>Supporting information</title><supplementary-material content-type="local-data" id="pone.0175582.s001"><label>S1 Table</label><caption><title>Numbering systems for reference sequence and mature collagen III.</title><p>This compares the systematic numbering and numbering from the start of the mature collagen as shown in the interactome.</p><p>(DOCX)</p></caption><media xlink:href="pone.0175582.s001.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0175582.s002"><label>S2 Table</label><caption><title>C-propeptide features and seqeunce variants.</title><p>This indicates features in the C-propeptide which is cleaved from the collagen III chain before it forms the interacome and the effect of pathogenic sequence variants.</p><p>(DOCX)</p></caption><media xlink:href="pone.0175582.s002.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We are grateful to Dr Richard Farndale provided novel unpublished ligands and their binding motifs on collagen III.</p></ack><ref-list><title>References</title><ref id="pone.0175582.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Ricard-Blum</surname><given-names>S</given-names></name> (<year>2011</year>) <article-title>The collagen family</article-title>. <source>Cold Spring Harb Perspect Biol</source><volume>3</volume>: <fpage>a004978</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1101/cshperspect.a004978">10.1101/cshperspect.a004978</ext-link></comment><pub-id pub-id-type="pmid">21421911</pub-id></mixed-citation></ref><ref id="pone.0175582.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Rich</surname><given-names>A</given-names></name>, <name><surname>Crick</surname><given-names>FH</given-names></name> (<year>1961</year>) <article-title>The molecular structure of collagen</article-title>. <source>J Mol Biol</source><volume>3</volume>: <fpage>483</fpage>–<lpage>506</lpage>. <pub-id pub-id-type="pmid">14491907</pub-id></mixed-citation></ref><ref id="pone.0175582.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>Meek</surname><given-names>KM</given-names></name>, <name><surname>Chapman</surname><given-names>JA</given-names></name>, <name><surname>Hardcastle</surname><given-names>RA</given-names></name> (<year>1979</year>) <article-title>The staining pattern of collagen fibrils. 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