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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
- Source :
- Journal of Biological Chemistry, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2012, 287 (39), pp.32630-9. ⟨10.1074/jbc.M112.387530⟩
- Publication Year :
- 2012
- Publisher :
- HAL CCSD, 2012.
-
Abstract
- International audience; 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.
- Subjects :
- HSC70 Heat-Shock Proteins
animal diseases
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Plasma protein binding
Protein Engineering
Biochemistry
chemistry.chemical_compound
MESH: Protein Structure, Tertiary
0302 clinical medicine
MESH: Saccharomyces cerevisiae Proteins
heterocyclic compounds
MESH: HSP70 Heat-Shock Proteins
Adenosine Triphosphatases
0303 health sciences
[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior
MESH: Peptides
[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Molecular Bases of Disease
Parkinson Disease
MESH: Saccharomyces cerevisiae
3. Good health
Cell biology
MESH: Protein Engineering
alpha-Synuclein
Binding domain
Protein Binding
Saccharomyces cerevisiae Proteins
Saccharomyces cerevisiae
MESH: Lewy Bodies
macromolecular substances
Biology
MESH: HSC70 Heat-Shock Proteins
Fibril
03 medical and health sciences
mental disorders
MESH: alpha-Synuclein
MESH: Adenosine Triphosphatases
Humans
MESH: Protein Binding
HSP70 Heat-Shock Proteins
Molecular Biology
030304 developmental biology
Alpha-synuclein
MESH: Humans
Cell Biology
Protein engineering
biology.organism_classification
Yeast
Protein Structure, Tertiary
nervous system diseases
MESH: Solubility
chemistry
Solubility
nervous system
Lewy Bodies
Peptides
030217 neurology & neurosurgery
MESH: Parkinson Disease
Subjects
Details
- Language :
- English
- ISSN :
- 00219258 and 1083351X
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry, Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2012, 287 (39), pp.32630-9. ⟨10.1074/jbc.M112.387530⟩
- Accession number :
- edsair.doi.dedup.....52c5a9078d4e1afecd86f0d933d81a67