title: 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.
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.
authors: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, 91198 Gif-sur-Yvette, France.
authors: Virginie
authors: V
authors: Redeker
authors: Samantha
authors: S
authors: Pemberton
authors: Willy
authors: W
authors: Bienvenut
authors: Luc
authors: L
authors: Bousset
authors: Ronald
authors: R
authors: Melki
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D010455:Peptides; C497604:SNCA protein, human; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D000251:Adenosine Triphosphatases; C095973:SSA1 protein, S cerevisiae