Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations
Identifieur interne : 000105 ( Pmc/Checkpoint ); précédent : 000104; suivant : 000106Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations
Auteurs : Federica Chiappori [Italie] ; Ivan Merelli [Italie] ; Giorgio Colombo [Italie] ; Luciano Milanesi [Italie] ; Giulia Morra [Italie]Source :
- PLoS Computational Biology [ 1553-734X ] ; 2012.
Abstract
Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.
Url:
DOI: 10.1371/journal.pcbi.1002844
PubMed: 23300424
PubMed Central: 3531320
Affiliations:
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Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano, Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano</wicri:regionArea><wicri:noRegion>Milano</wicri:noRegion></affiliation></author><author><name sortKey="Milanesi, Luciano" sort="Milanesi, Luciano" uniqKey="Milanesi L" first="Luciano" last="Milanesi">Luciano Milanesi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi)</wicri:regionArea><wicri:noRegion>Segrate (Mi)</wicri:noRegion></affiliation></author><author><name sortKey="Morra, Giulia" sort="Morra, Giulia" uniqKey="Morra G" first="Giulia" last="Morra">Giulia Morra</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano, Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano</wicri:regionArea><wicri:noRegion>Milano</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23300424</idno><idno type="pmc">3531320</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531320</idno><idno type="RBID">PMC:3531320</idno><idno type="doi">10.1371/journal.pcbi.1002844</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000301</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000301</idno><idno type="wicri:Area/Pmc/Curation">000189</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000189</idno><idno type="wicri:Area/Pmc/Checkpoint">000105</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000105</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations</title><author><name sortKey="Chiappori, Federica" sort="Chiappori, Federica" uniqKey="Chiappori F" first="Federica" last="Chiappori">Federica Chiappori</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi)</wicri:regionArea><wicri:noRegion>Segrate (Mi)</wicri:noRegion></affiliation></author><author><name sortKey="Merelli, Ivan" sort="Merelli, Ivan" uniqKey="Merelli I" first="Ivan" last="Merelli">Ivan Merelli</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi)</wicri:regionArea><wicri:noRegion>Segrate (Mi)</wicri:noRegion></affiliation></author><author><name sortKey="Colombo, Giorgio" sort="Colombo, Giorgio" uniqKey="Colombo G" first="Giorgio" last="Colombo">Giorgio Colombo</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano, Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano</wicri:regionArea><wicri:noRegion>Milano</wicri:noRegion></affiliation></author><author><name sortKey="Milanesi, Luciano" sort="Milanesi, Luciano" uniqKey="Milanesi L" first="Luciano" last="Milanesi">Luciano Milanesi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi)</wicri:regionArea><wicri:noRegion>Segrate (Mi)</wicri:noRegion></affiliation></author><author><name sortKey="Morra, Giulia" sort="Morra, Giulia" uniqKey="Morra G" first="Giulia" last="Morra">Giulia Morra</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano, Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano</wicri:regionArea><wicri:noRegion>Milano</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS Computational Biology</title><idno type="ISSN">1553-734X</idno><idno type="eISSN">1553-7358</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Young, Jc" uniqKey="Young J">JC Young</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mayer, Mp" uniqKey="Mayer M">MP Mayer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luders, J" uniqKey="Luders J">J Lüders</name></author><author><name sortKey="Demand, J" uniqKey="Demand J">J Demand</name></author><author><name sortKey="Hohfeld, J" uniqKey="Hohfeld J">J Höhfeld</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mayer, Mp" uniqKey="Mayer M">MP Mayer</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Comput Biol</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Comput. Biol</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">ploscomp</journal-id><journal-title-group><journal-title>PLoS Computational Biology</journal-title></journal-title-group><issn pub-type="ppub">1553-734X</issn><issn pub-type="epub">1553-7358</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23300424</article-id><article-id pub-id-type="pmc">3531320</article-id><article-id pub-id-type="publisher-id">PCOMPBIOL-D-12-01013</article-id><article-id pub-id-type="doi">10.1371/journal.pcbi.1002844</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Biochemistry</subject></subj-group><subj-group><subject>Biophysics</subject></subj-group><subj-group><subject>Computational Biology</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Chemistry</subject><subj-group><subject>Chemical Biology</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Physics</subject><subj-group><subject>Biophysics</subject></subj-group></subj-group></article-categories><title-group><article-title>Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations</article-title><alt-title alt-title-type="running-head">Molecular Basis of Hsp70 Allostery</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chiappori</surname><given-names>Federica</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Merelli</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Colombo</surname><given-names>Giorgio</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milanesi</surname><given-names>Luciano</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Morra</surname><given-names>Giulia</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Istituto di Tecnologie Biomediche – Consiglio Nazionale delle Ricerche (ITB-CNR), Segrate (Mi), Italy</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Istituto di Chimica del Riconoscimento Molecolare - Consiglio Nazionale delle Ricerche (ICRM-CNR), Milano, Italy</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Cui</surname><given-names>Qiang</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Wisconsin, Madison, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>luciano.milanesi@itb.cnr.it</email> (LM); <email>giulia.morra@icrm.cnr.it</email> (GM)</corresp><fn fn-type="conflict"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: GC GM FC IM. Performed the experiments: FC GM IM. Analyzed the data: FC GM. Contributed reagents/materials/analysis tools: IM GC LM. Wrote the paper: FC GM GC. Coordinated the research: GC LM Critically reviewed the manuscript: IM LM.</p></fn></author-notes><pub-date pub-type="collection"><month>12</month><year>2012</year></pub-date><pmc-comment> Fake ppub added to accomodate plos workflow change from 03/2008 and 03/2009 </pmc-comment>
<pub-date pub-type="ppub"><month>12</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>27</day><month>12</month><year>2012</year></pub-date><volume>8</volume><issue>12</issue><elocation-id>e1002844</elocation-id><history><date date-type="received"><day>20</day><month>6</month><year>2012</year></date><date date-type="accepted"><day>2</day><month>11</month><year>2012</year></date></history><permissions><copyright-year>2012</copyright-year><copyright-holder>Chiappori et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Allostery, or the capability of proteins to respond to ligand binding events with a variation in structure or dynamics at a distant site, is a common feature for biomolecular function and regulation in a large number of proteins. Intra-protein connections and inter-residue coordinations underlie allosteric mechanisms and react to binding primarily through a finely tuned modulation of motions and structures at the microscopic scale. Hence, all-atom molecular dynamics simulations are suitable to investigate the molecular basis of allostery. Moreover, understanding intra-protein communication pathways at atomistic resolutions offers unique opportunities in rational drug design. Proteins of the Hsp70 family are allosteric molecular chaperones involved in maintaining cellular protein homeostasis. These proteins are involved in several types of cancer, neurodegenerative diseases, aging and infections and are therefore pharmaceutically relevant targets. In this work we have analyzed, by multiple molecular dynamics simulations, the long-range dynamical and conformational effects of ligands bound to Hsp70, and found relevant differences in comparison to the known non-allosteric structural homolog Hsp110. The resulting model of the mechanism of allosteric propagation offers the opportunity of identifying on-pathway allosteric druggable sites, which we propose could guide rational drug-design efforts targeting Hsp70.</p></abstract><funding-group><funding-statement>This work has been supported by the Italian Ministry of Education and Research through the Flagship (PB05) “InterOmics”, ITALBIONET (RBPR05ZK2Z), HIRMA (RBAP11YS7K) and the European “MIMOMICS” projects. GC acknowledges support from AIRC (Italian Association for Cancer Research) project IG.11775 and from Fondazione Cariplo through the CHECOSP project 2011.1800. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="15"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>Italie</li></country></list><tree><country name="Italie"><noRegion><name sortKey="Chiappori, Federica" sort="Chiappori, Federica" uniqKey="Chiappori F" first="Federica" last="Chiappori">Federica Chiappori</name></noRegion><name sortKey="Colombo, Giorgio" sort="Colombo, Giorgio" uniqKey="Colombo G" first="Giorgio" last="Colombo">Giorgio Colombo</name><name sortKey="Merelli, Ivan" sort="Merelli, Ivan" uniqKey="Merelli I" first="Ivan" last="Merelli">Ivan Merelli</name><name sortKey="Milanesi, Luciano" sort="Milanesi, Luciano" uniqKey="Milanesi L" first="Luciano" last="Milanesi">Luciano Milanesi</name><name sortKey="Morra, Giulia" sort="Morra, Giulia" uniqKey="Morra G" first="Giulia" last="Morra">Giulia Morra</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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