title: Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of alpha-synuclein, a molecular chaperone.
abstract: alpha-Synuclein, an acidic neuronal protein of 140 amino acids, is extremely heat-resistant and is natively unfolded. Recent studies have demonstrated that alpha-synuclein has chaperone activity both in vitro and in vivo, and that this activity is lost upon removing its C-terminal acidic tail. However, the detailed mechanism of the chaperone action of alpha-synuclein remains unknown. In this study, we investigated the molecular mechanism of the chaperone action of alpha-synuclein by analyzing the roles of its N-terminal and C-terminal domains. The N-terminal domain (residues 1-95) was found to bind to substrate proteins to form high molecular weight complexes, whereas the C-terminal acidic tail (residues 96-140) appears to be primarily involved in solubilizing the high molecular weight complexes. Because the substrate-binding domain and the solubilizing domain for chaperone function are well separated in alpha-synuclein, the N-terminal-binding domain can be substituted by other proteins or peptides. Interestingly, the resultant engineered chaperone proteins appeared to display differential efficiency and specificity in terms of the chaperone function, which depended upon the nature of the binding domain. This finding implies that the C-terminal acidic tail of alpha-synuclein can be fused with other proteins or peptides to engineer synthetic chaperones for specific purposes.
authors.affiliation: Department of Microbiology and Brain Korea 21 Project of Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
authors.forename: Han Young
authors.initials: HY
authors.lastname: Jung
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Kim
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.forename: Chul-Hak
authors.initials: CH
authors.lastname: Yang
authors.forename: Jongsun
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000378:metabolism; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity; D051843:Synucleins; D013696:Temperature; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D013997:Time Factors; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D013762:Tetrahydrofolate Dehydrogenase; D005982:Glutathione Transferase