Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease
Identifieur interne : 000005 ( Pmc/Checkpoint ); précédent : 000004; suivant : 000006Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease
Auteurs : Nicholas P. Schafer [Danemark] ; Ha H. Truong ; Daniel E. Otzen [Danemark] ; Kresten Lindorff-Larsen [Danemark] ; Peter G. WolynesSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2016.
Abstract
Membrane proteins perform diverse functions in the cell while being embedded in lipid bilayers, but the presence of the anisotropic, nonpolar membrane environment has slowed progress in understanding how these proteins fold and function. Herein, we study GlpG, an intramembrane protease, using computationally efficient models to fill in structural details that are currently invisible to experimental techniques and inaccessible to atomistic simulations. We find that GlpG’s modular functional architecture leaves an imprint throughout its folding and functional landscape, leading to multiple possible folding pathways and the population of near-native states with functional significance. We propose a mechanism by which destabilizing mutations can accelerate folding in detergent micelles, a previously puzzling experimental observation.
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DOI: 10.1073/pnas.1524027113
PubMed: 26858402
PubMed Central: 4776503
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Truong</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005;</nlm:aff></affiliation></author><author><name sortKey="Otzen, Daniel E" sort="Otzen, Daniel E" uniqKey="Otzen D" first="Daniel E." last="Otzen">Daniel E. Otzen</name><affiliation wicri:level="1"><nlm:aff id="aff1">Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics,<institution>Aarhus University</institution>, DK-8000 Aarhus,<country>Denmark</country>;</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lindorff Larsen, Kresten" sort="Lindorff Larsen, Kresten" uniqKey="Lindorff Larsen K" first="Kresten" last="Lindorff-Larsen">Kresten Lindorff-Larsen</name><affiliation wicri:level="1"><nlm:aff id="aff3">The Linderstrøm-Lang Centre for Protein Science, Department of Biology,<institution>University of Copenhagen</institution>, DK-2200 Copenhagen,<country>Denmark</country></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wolynes, Peter G" sort="Wolynes, Peter G" uniqKey="Wolynes P" first="Peter G." last="Wolynes">Peter G. Wolynes</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26858402</idno><idno type="pmc">4776503</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776503</idno><idno type="RBID">PMC:4776503</idno><idno type="doi">10.1073/pnas.1524027113</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000104</idno><idno type="wicri:Area/Pmc/Curation">000104</idno><idno type="wicri:Area/Pmc/Checkpoint">000005</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease</title><author><name sortKey="Schafer, Nicholas P" sort="Schafer, Nicholas P" uniqKey="Schafer N" first="Nicholas P." last="Schafer">Nicholas P. Schafer</name><affiliation wicri:level="1"><nlm:aff id="aff1">Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics,<institution>Aarhus University</institution>, DK-8000 Aarhus,<country>Denmark</country>;</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Truong, Ha H" sort="Truong, Ha H" uniqKey="Truong H" first="Ha H." last="Truong">Ha H. Truong</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005;</nlm:aff></affiliation></author><author><name sortKey="Otzen, Daniel E" sort="Otzen, Daniel E" uniqKey="Otzen D" first="Daniel E." last="Otzen">Daniel E. Otzen</name><affiliation wicri:level="1"><nlm:aff id="aff1">Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics,<institution>Aarhus University</institution>, DK-8000 Aarhus,<country>Denmark</country>;</nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lindorff Larsen, Kresten" sort="Lindorff Larsen, Kresten" uniqKey="Lindorff Larsen K" first="Kresten" last="Lindorff-Larsen">Kresten Lindorff-Larsen</name><affiliation wicri:level="1"><nlm:aff id="aff3">The Linderstrøm-Lang Centre for Protein Science, Department of Biology,<institution>University of Copenhagen</institution>, DK-2200 Copenhagen,<country>Denmark</country></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wolynes, Peter G" sort="Wolynes, Peter G" uniqKey="Wolynes P" first="Peter G." last="Wolynes">Peter G. Wolynes</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Membrane proteins perform diverse functions in the cell while being embedded in lipid bilayers, but the presence of the anisotropic, nonpolar membrane environment has slowed progress in understanding how these proteins fold and function. Herein, we study GlpG, an intramembrane protease, using computationally efficient models to fill in structural details that are currently invisible to experimental techniques and inaccessible to atomistic simulations. We find that GlpG’s modular functional architecture leaves an imprint throughout its folding and functional landscape, leading to multiple possible folding pathways and the population of near-native states with functional significance. We propose a mechanism by which destabilizing mutations can accelerate folding in detergent micelles, a previously puzzling experimental observation.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26858402</article-id><article-id pub-id-type="pmc">4776503</article-id><article-id pub-id-type="publisher-id">201524027</article-id><article-id pub-id-type="doi">10.1073/pnas.1524027113</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biophysics and Computational Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease</article-title><alt-title alt-title-type="short">Constraints and modular structure in GlpG folding</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schafer</surname><given-names>Nicholas P.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Truong</surname><given-names>Ha H.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Otzen</surname><given-names>Daniel E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lindorff-Larsen</surname><given-names>Kresten</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wolynes</surname><given-names>Peter G.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics,<institution>Aarhus University</institution>, DK-8000 Aarhus,<country>Denmark</country>;</aff><aff id="aff2"><sup>b</sup>Department of Chemistry, Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005;</aff><aff id="aff3"><sup>c</sup>The Linderstrøm-Lang Centre for Protein Science, Department of Biology,<institution>University of Copenhagen</institution>, DK-2200 Copenhagen,<country>Denmark</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. Email: <email>lindorff@bio.ku.dk</email> or <email>pwolynes@rice.edu</email>.</corresp><fn fn-type="edited-by"><p>Contributed by Peter G. Wolynes, January 6, 2016 (sent for review December 7, 2015; reviewed by James U. Bowie and Heedeok Hong)</p></fn><fn fn-type="con"><p>Author contributions: N.P.S., H.H.T., D.E.O., K.L.-L., and P.G.W. designed research; N.P.S. and H.H.T. performed research; N.P.S. and H.H.T. contributed new reagents/analytic tools; N.P.S., H.H.T., D.E.O., K.L.-L., and P.G.W. analyzed data; and N.P.S., H.H.T., D.E.O., K.L.-L., and P.G.W. wrote the paper.</p></fn><fn fn-type="con"><p>Reviewers: J.U.B., University of California, Los Angeles; and H.H., Michigan State University.</p></fn></author-notes><pub-date pub-type="ppub"><day>23</day><month>2</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>8</day><month>2</month><year>2016</year></pub-date><volume>113</volume><issue>8</issue><fpage>2098</fpage><lpage>2103</lpage><permissions></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201524027.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Membrane proteins perform diverse functions in the cell while being embedded in lipid bilayers, but the presence of the anisotropic, nonpolar membrane environment has slowed progress in understanding how these proteins fold and function. Herein, we study GlpG, an intramembrane protease, using computationally efficient models to fill in structural details that are currently invisible to experimental techniques and inaccessible to atomistic simulations. We find that GlpG’s modular functional architecture leaves an imprint throughout its folding and functional landscape, leading to multiple possible folding pathways and the population of near-native states with functional significance. We propose a mechanism by which destabilizing mutations can accelerate folding in detergent micelles, a previously puzzling experimental observation.</p></abstract><abstract><p>We investigate the folding of GlpG, an intramembrane protease, using perfectly funneled structure-based models that implicitly account for the absence or presence of the membrane. These two models are used to describe, respectively, folding in detergent micelles and folding within a bilayer, which effectively constrains GlpG's topology in unfolded and partially folded states. Structural free-energy landscape analysis shows that although the presence of multiple folding pathways is an intrinsic property of GlpG’s modular functional architecture, the large entropic cost of organizing helical bundles in the absence of the constraining bilayer leads to pathways that backtrack (i.e., local unfolding of previously folded substructures is required when moving from the unfolded to the folded state along the minimum free-energy pathway). This backtracking explains the experimental observation of thermodynamically destabilizing mutations that accelerate GlpG’s folding in detergent micelles. In contrast, backtracking is absent from the model when folding is constrained within a bilayer, the environment in which GlpG has evolved to fold. We also characterize a near-native state with a highly mobile transmembrane helix 5 (TM5) that is significantly populated under folding conditions when GlpG is embedded in a bilayer. Unbinding of TM5 from the rest of the structure exposes GlpG’s active site, consistent with studies of the catalytic mechanism of GlpG that suggest that TM5 serves as a substrate gate to the active site.</p></abstract><kwd-group><kwd>membrane proteins</kwd><kwd>micelle folding</kwd><kwd>bilayer folding</kwd><kwd>folding mechanism</kwd><kwd>intramembrane proteolysis</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">HHS | NIH | National Institute of General Medical Sciences (NIGMS)<named-content content-type="funder-id">100000057</named-content></funding-source><award-id rid="sp1">R01 GM44557</award-id></award-group><award-group id="gs2"><funding-source id="sp2">Novo Nordisk<named-content content-type="funder-id">501100004191</named-content></funding-source></award-group><award-group id="gs3"><funding-source id="sp3">Carlsbergfondet (Carlsberg Foundation)<named-content content-type="funder-id">501100002808</named-content></funding-source><award-id rid="sp3">CF14-0287</award-id></award-group><award-group id="gs4"><funding-source id="sp4">Danish National Research Foundation (Danmarks Grundforskningsfond)<named-content content-type="funder-id">501100001732</named-content></funding-source><award-id rid="sp4">DFF-4090-00220</award-id></award-group><award-group id="gs5"><funding-source id="sp5">National Science Foundation (NSF)<named-content content-type="funder-id">100000001</named-content></funding-source><award-id rid="sp5">OCI-0959097</award-id></award-group></funding-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>Danemark</li></country></list><tree><noCountry><name sortKey="Truong, Ha H" sort="Truong, Ha H" uniqKey="Truong H" first="Ha H." last="Truong">Ha H. Truong</name><name sortKey="Wolynes, Peter G" sort="Wolynes, Peter G" uniqKey="Wolynes P" first="Peter G." last="Wolynes">Peter G. Wolynes</name></noCountry><country name="Danemark"><noRegion><name sortKey="Schafer, Nicholas P" sort="Schafer, Nicholas P" uniqKey="Schafer N" first="Nicholas P." last="Schafer">Nicholas P. Schafer</name></noRegion><name sortKey="Lindorff Larsen, Kresten" sort="Lindorff Larsen, Kresten" uniqKey="Lindorff Larsen K" first="Kresten" last="Lindorff-Larsen">Kresten Lindorff-Larsen</name><name sortKey="Otzen, Daniel E" sort="Otzen, Daniel E" uniqKey="Otzen D" first="Daniel E." last="Otzen">Daniel E. Otzen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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