Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation*
Identifieur interne : 001601 ( Ncbi/Merge ); précédent : 001600; suivant : 001602Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation*
Auteurs : Elodie Monsellier [France] ; Virginie Redeker [France] ; Gemma Ruiz-Arlandis [France] ; Luc Bousset [France] ; Ronald Melki [France]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2014.
Abstract
Url:
DOI: 10.1074/jbc.M114.603332
PubMed: 25505179
PubMed Central: 4317008
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<author><name sortKey="Monsellier, Elodie" sort="Monsellier, Elodie" uniqKey="Monsellier E" first="Elodie" last="Monsellier">Elodie Monsellier</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
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<author><name sortKey="Redeker, Virginie" sort="Redeker, Virginie" uniqKey="Redeker V" first="Virginie" last="Redeker">Virginie Redeker</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
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<author><name sortKey="Ruiz Arlandis, Gemma" sort="Ruiz Arlandis, Gemma" uniqKey="Ruiz Arlandis G" first="Gemma" last="Ruiz-Arlandis">Gemma Ruiz-Arlandis</name>
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<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
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<author><name sortKey="Bousset, Luc" sort="Bousset, Luc" uniqKey="Bousset L" first="Luc" last="Bousset">Luc Bousset</name>
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<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
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<author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation<xref ref-type="fn" rid="FN1">*</xref>
</title>
<author><name sortKey="Monsellier, Elodie" sort="Monsellier, Elodie" uniqKey="Monsellier E" first="Elodie" last="Monsellier">Elodie Monsellier</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Redeker, Virginie" sort="Redeker, Virginie" uniqKey="Redeker V" first="Virginie" last="Redeker">Virginie Redeker</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ruiz Arlandis, Gemma" sort="Ruiz Arlandis, Gemma" uniqKey="Ruiz Arlandis G" first="Gemma" last="Ruiz-Arlandis">Gemma Ruiz-Arlandis</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bousset, Luc" sort="Bousset, Luc" uniqKey="Bousset L" first="Luc" last="Bousset">Luc Bousset</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
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<series><title level="j">The Journal of Biological Chemistry</title>
<idno type="ISSN">0021-9258</idno>
<idno type="eISSN">1083-351X</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p><bold>Background:</bold>
Hsc70 has an alleviating effect on the toxicity of polyglutamine (polyQ)-containing proteins <italic>in vivo</italic>
.</p>
<p><bold>Results:</bold>
Hsc70 binds specifically the N-terminal flank of huntingtin exon 1.</p>
<p><bold>Conclusion:</bold>
Hsc70 interaction with huntingtin exon 1 N-terminal flank affects the conformation of the resulting assemblies.</p>
<p><bold>Significance:</bold>
We identify the surface interfaces between Hsc70 and huntingtin exon 1, which allows the design of future therapeutic tools.</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">J Biol Chem</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id>
<journal-id journal-id-type="hwp">jbc</journal-id>
<journal-id journal-id-type="pmc">jbc</journal-id>
<journal-id journal-id-type="publisher-id">JBC</journal-id>
<journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title>
</journal-title-group>
<issn pub-type="ppub">0021-9258</issn>
<issn pub-type="epub">1083-351X</issn>
<publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name>
<publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25505179</article-id>
<article-id pub-id-type="pmc">4317008</article-id>
<article-id pub-id-type="publisher-id">M114.603332</article-id>
<article-id pub-id-type="doi">10.1074/jbc.M114.603332</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Molecular Bases of Disease</subject>
</subj-group>
</article-categories>
<title-group><article-title>Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation<xref ref-type="fn" rid="FN1">*</xref>
</article-title>
<alt-title alt-title-type="short">Molecular Interaction between Hsc70 and Huntingtin Exon 1</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Monsellier</surname>
<given-names>Elodie</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Redeker</surname>
<given-names>Virginie</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ruiz-Arlandis</surname>
<given-names>Gemma</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bousset</surname>
<given-names>Luc</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Melki</surname>
<given-names>Ronald</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="corresp" rid="cor2"><sup>2</sup>
</xref>
</contrib>
<aff id="aff1">From the Neuroscience Paris-Saclay Institute, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>1</label>
To whom correspondence may be addressed. Tel.: <phone>33-16982-3486</phone>
; E-mail: <email>monsellier@lebs.cnrs-gif.fr</email>
.</corresp>
<corresp id="cor2"><label>2</label>
To whom correspondence may be addressed. Tel.: <phone>33-16982-3503</phone>
; E-mail: <email>melki@lebs.cnrs-gif.fr</email>
.</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>30</day>
<month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>10</day>
<month>12</month>
<year>2014</year>
</pub-date>
<volume>290</volume>
<issue>5</issue>
<fpage>2560</fpage>
<lpage>2576</lpage>
<history><date date-type="received"><day>26</day>
<month>8</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>18</day>
<month>11</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.</copyright-statement>
<copyright-year>2015</copyright-year>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc00515002560.pdf"></self-uri>
<abstract abstract-type="teaser"><p><bold>Background:</bold>
Hsc70 has an alleviating effect on the toxicity of polyglutamine (polyQ)-containing proteins <italic>in vivo</italic>
.</p>
<p><bold>Results:</bold>
Hsc70 binds specifically the N-terminal flank of huntingtin exon 1.</p>
<p><bold>Conclusion:</bold>
Hsc70 interaction with huntingtin exon 1 N-terminal flank affects the conformation of the resulting assemblies.</p>
<p><bold>Significance:</bold>
We identify the surface interfaces between Hsc70 and huntingtin exon 1, which allows the design of future therapeutic tools.</p>
</abstract>
<abstract><p>The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ-containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease.</p>
</abstract>
<kwd-group><kwd>Heat Shock Protein (HSP)</kwd>
<kwd>Huntington Disease</kwd>
<kwd>Mass Spectrometry (MS)</kwd>
<kwd>Molecular Chaperone</kwd>
<kwd>Neurodegenerative Disease</kwd>
<kwd>Polyglutamine</kwd>
<kwd>Protein Aggregation</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>France</li>
</country>
<region><li>Île-de-France</li>
</region>
<settlement><li>Gif-sur-Yvette</li>
</settlement>
</list>
<tree><country name="France"><region name="Île-de-France"><name sortKey="Monsellier, Elodie" sort="Monsellier, Elodie" uniqKey="Monsellier E" first="Elodie" last="Monsellier">Elodie Monsellier</name>
</region>
<name sortKey="Bousset, Luc" sort="Bousset, Luc" uniqKey="Bousset L" first="Luc" last="Bousset">Luc Bousset</name>
<name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
<name sortKey="Redeker, Virginie" sort="Redeker, Virginie" uniqKey="Redeker V" first="Virginie" last="Redeker">Virginie Redeker</name>
<name sortKey="Ruiz Arlandis, Gemma" sort="Ruiz Arlandis, Gemma" uniqKey="Ruiz Arlandis G" first="Gemma" last="Ruiz-Arlandis">Gemma Ruiz-Arlandis</name>
</country>
</tree>
</affiliations>
</record>
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