ATPase Subdomain IA Is a Mediator of Interdomain Allostery in Hsp70 Molecular Chaperones
Identifieur interne : 000258 ( Pmc/Curation ); précédent : 000257; suivant : 000259ATPase Subdomain IA Is a Mediator of Interdomain Allostery in Hsp70 Molecular Chaperones
Auteurs : Ignacio J. General [États-Unis] ; Ying Liu [États-Unis] ; Mandy E. Blackburn [États-Unis] ; Wenzhi Mao [États-Unis, République populaire de Chine] ; Lila M. Gierasch [États-Unis] ; Ivet Bahar [États-Unis]Source :
- PLoS Computational Biology [ 1553-734X ] ; 2014.
Abstract
The versatile functions of the heat shock protein 70 (Hsp70) family of molecular chaperones rely on allosteric interactions between their nucleotide-binding and substrate-binding domains, NBD and SBD. Understanding the mechanism of interdomain allostery is essential to rational design of Hsp70 modulators. Yet, despite significant progress in recent years, how the two Hsp70 domains regulate each other's activity remains elusive. Covariance data from experiments and computations emerged in recent years as valuable sources of information towards gaining insights into the molecular events that mediate allostery. In the present study, conservation and covariance properties derived from both sequence and structural dynamics data are integrated with results from Perturbation Response Scanning and
Url:
DOI: 10.1371/journal.pcbi.1003624
PubMed: 24831085
PubMed Central: 4022485
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<front><div type="abstract" xml:lang="en"><p>The versatile functions of the heat shock protein 70 (Hsp70) family of molecular chaperones rely on allosteric interactions between their nucleotide-binding and substrate-binding domains, NBD and SBD. Understanding the mechanism of interdomain allostery is essential to rational design of Hsp70 modulators. Yet, despite significant progress in recent years, how the two Hsp70 domains regulate each other's activity remains elusive. Covariance data from experiments and computations emerged in recent years as valuable sources of information towards gaining insights into the molecular events that mediate allostery. In the present study, conservation and covariance properties derived from both sequence and structural dynamics data are integrated with results from Perturbation Response Scanning and <italic>in vivo</italic>
functional assays, so as to establish the dynamical basis of interdomain signal transduction in Hsp70s. Our study highlights the critical roles of SBD residues D481 and T417 in mediating the coupled motions of the two domains, as well as that of G506 in enabling the movements of the α-helical lid with respect to the β-sandwich. It also draws attention to the distinctive role of the NBD subdomains: Subdomain IA acts as a key mediator of signal transduction between the ATP- and substrate-binding sites, this function being achieved by a cascade of interactions predominantly involving conserved residues such as V139, D148, R167 and K155. Subdomain IIA, on the other hand, is distinguished by strong coevolutionary signals (with the SBD) exhibited by a series of residues (D211, E217, L219, T383) implicated in DnaJ recognition. The occurrence of coevolving residues at the DnaJ recognition region parallels the behavior recently observed at the nucleotide-exchange-factor recognition region of subdomain IIB. These findings suggest that Hsp70 tends to adapt to co-chaperone recognition and activity via coevolving residues, whereas interdomain allostery, critical to chaperoning, is robustly enabled by conserved interactions.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<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">24831085</article-id>
<article-id pub-id-type="pmc">4022485</article-id>
<article-id pub-id-type="publisher-id">PCOMPBIOL-D-13-01739</article-id>
<article-id pub-id-type="doi">10.1371/journal.pcbi.1003624</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 and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Chaperone Proteins</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Computational Biology</subject>
</subj-group>
<subj-group><subject>Molecular Biology</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Sequencing Techniques</subject>
<subj-group><subject>Sequence Analysis</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>ATPase Subdomain IA Is a Mediator of Interdomain Allostery in Hsp70 Molecular Chaperones</article-title>
<alt-title alt-title-type="running-head">Allostery in Hsp70 Molecular Chaperones</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>General</surname>
<given-names>Ignacio J.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Ying</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Blackburn</surname>
<given-names>Mandy E.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mao</surname>
<given-names>Wenzhi</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gierasch</surname>
<given-names>Lila M.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bahar</surname>
<given-names>Ivet</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Department of Biochemistry & Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Pharmacology, Tsinghua University, Beijing, China</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Verkhivker</surname>
<given-names>Gennady M.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>Chapman University, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>bahar@pitt.edu</email>
</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: LMG IB. Performed the experiments: IJG YL MEB WM. Analyzed the data: IJG YL MEB WM LMG IB. Contributed reagents/materials/analysis tools: LMG IJG WM IB. Wrote the paper: IJG MEB LMG IB.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>5</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>15</day>
<month>5</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>5</issue>
<elocation-id>e1003624</elocation-id>
<history><date date-type="received"><day>3</day>
<month>10</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>31</day>
<month>3</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 General et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>General 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 Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>The versatile functions of the heat shock protein 70 (Hsp70) family of molecular chaperones rely on allosteric interactions between their nucleotide-binding and substrate-binding domains, NBD and SBD. Understanding the mechanism of interdomain allostery is essential to rational design of Hsp70 modulators. Yet, despite significant progress in recent years, how the two Hsp70 domains regulate each other's activity remains elusive. Covariance data from experiments and computations emerged in recent years as valuable sources of information towards gaining insights into the molecular events that mediate allostery. In the present study, conservation and covariance properties derived from both sequence and structural dynamics data are integrated with results from Perturbation Response Scanning and <italic>in vivo</italic>
functional assays, so as to establish the dynamical basis of interdomain signal transduction in Hsp70s. Our study highlights the critical roles of SBD residues D481 and T417 in mediating the coupled motions of the two domains, as well as that of G506 in enabling the movements of the α-helical lid with respect to the β-sandwich. It also draws attention to the distinctive role of the NBD subdomains: Subdomain IA acts as a key mediator of signal transduction between the ATP- and substrate-binding sites, this function being achieved by a cascade of interactions predominantly involving conserved residues such as V139, D148, R167 and K155. Subdomain IIA, on the other hand, is distinguished by strong coevolutionary signals (with the SBD) exhibited by a series of residues (D211, E217, L219, T383) implicated in DnaJ recognition. The occurrence of coevolving residues at the DnaJ recognition region parallels the behavior recently observed at the nucleotide-exchange-factor recognition region of subdomain IIB. These findings suggest that Hsp70 tends to adapt to co-chaperone recognition and activity via coevolving residues, whereas interdomain allostery, critical to chaperoning, is robustly enabled by conserved interactions.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>The Hsp70 family of molecular chaperones assists in protein folding, degradation, assembly/disassembly of some complexes, and intracellular trafficking. These activities in the cell are accomplished by coupled conformational switches/signals between their nucleotide-binding and substrate-binding domains (NBD and SBD), assisted by cognate co-chaperones. Despite significant progress in the field, the molecular basis of Hsp70 machinery and the key interactions that regulate interdomain communication are not fully understood. Using a combination of experimental and computational methods, including <italic>in vivo</italic>
functional assays, sequence- and structure-based analyses and perturbation response scanning, we identified a network of conserved interactions in subdomain IA of the NBD, which plays a key (<italic>effector</italic>
) role in propagating signals between the ATP-binding and substrate-binding sites. Subdomain IIA, on the other hand, appears to adapt to J-domain co-chaperone binding by virtue of a broadly distributed cluster of co-evolving residues on the recognition surface.</p>
</abstract>
<funding-group><funding-statement>This work was supported by NIH (<ext-link ext-link-type="uri" xlink:href="http://www.nih.gov">www.nih.gov</ext-link>
), grants GM099738 and GM103712 to IB, and GM027616-34 to LMG. 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="17"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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