ParkinsonFranceV1, Hal, Curation, bibRecord, 000517

Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p.

Identifieur interne : 000517 ( Hal/Curation ); précédent : 000516; suivant : 000518

Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p.

Auteurs : Virginie Redeker [France] ; Samantha Pemberton [France] ; Willy Bienvenut [France] ; Luc Bousset [France] ; Ronald Melki [France]

Source :

Journal of Biological Chemistry [ 0021-9258 ] ; 2012-09-21.

RBID : Hal:hal-01183065

Abstract

Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.

Url:

https://hal.archives-ouvertes.fr/hal-01183065

DOI: 10.1074/jbc.M112.387530

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Le document en format XML

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<front><div type="abstract" xml:lang="en">Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.</div>
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          <profileDesc>            <langUsage>              <language ident="en">English</language>
            </langUsage>
            <textClass>              <classCode scheme="mesh">Adenosine Triphosphatases</classCode>
              <classCode scheme="mesh">HSC70 Heat-Shock Proteins</classCode>
              <classCode scheme="mesh">Saccharomyces cerevisiae</classCode>
              <classCode scheme="mesh">Saccharomyces cerevisiae Proteins</classCode>
              <classCode scheme="mesh">Solubility</classCode>
              <classCode scheme="mesh">alpha-Synuclein</classCode>
              <classCode scheme="mesh">HSP70 Heat-Shock Proteins</classCode>
              <classCode scheme="mesh">Humans</classCode>
              <classCode scheme="mesh">Lewy Bodies</classCode>
              <classCode scheme="mesh">Parkinson Disease</classCode>
              <classCode scheme="mesh">Peptides</classCode>
              <classCode scheme="mesh">Protein Binding</classCode>
              <classCode scheme="mesh">Protein Engineering</classCode>
              <classCode scheme="mesh">Protein Structure, Tertiary</classCode>
              <classCode scheme="halDomain" n="sdv.neu.nb">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology</classCode>
              <classCode scheme="halDomain" n="sdv.neu.pc">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior</classCode>
              <classCode scheme="halDomain" n="sdv.neu.sc">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences</classCode>
              <classCode scheme="halTypology" n="ART">Journal articles</classCode>
            </textClass>
            <abstract xml:lang="en">Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.</abstract>
          </profileDesc>
        </hal>
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	La maladie de Parkinson en France (serveur d'exploration)
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La maladie de Parkinson en France (serveur d'exploration)

Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p.

Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p.

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