title: The role of the acidic domain of α-synuclein in amyloid fibril formation: a molecular dynamics study.
abstract: The detailed mechanism of the pathology of α-synuclein in the Parkinson's disease has not been clearly elucidated. Recent studies suggested a possible chaperone-like role of the acidic C-terminal region of α-synuclein in the formation of amyloid fibrils. It was also previously demonstrated that the α-synuclein amyloid fibril formation is accelerated by mutations of proline residues to alanine in the acidic region. We performed replica exchange molecular dynamics simulations of the acidic and nonamyloid component (NAC) domains of the wild type and proline-to-alanine mutants of α-synuclein under various conditions. Our results showed that structural changes induced by a change in pH or an introduction of mutations lead to a reduction in mutual contacts between the NAC and acidic regions. Our data suggest that the highly charged acidic region of α-synuclein may act as an intramolecular chaperone by protecting the hydrophobic domain from aggregation. Understanding the function of such chaperone-like parts of fibril-forming proteins may provide novel insights into the mechanism of amyloid formation.
authors: a Department of Chemistry , Seoul National University , Seoul 151-747 , Republic of Korea.
authors: SeongByeong
authors: S
authors: Park
authors: a Department of Chemistry , Seoul National University , Seoul 151-747 , Republic of Korea.
authors: Jeseong
authors: J
authors: Yoon
authors: b Department of Chemistry , Sejong University , Seoul 143-747 , Republic of Korea.
authors: Soonmin
authors: S
authors: Jang
authors: b Department of Chemistry , Sejong University , Seoul 143-747 , Republic of Korea.
authors: Kyunghee
authors: K
authors: Lee
authors: a Department of Chemistry , Seoul National University , Seoul 151-747 , Republic of Korea.
authors: Seokmin
authors: S
authors: Shin
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D050505:Mutant Proteins; D051844:alpha-Synuclein
keywords: amyloid formation; intramolecular chaperone; molecular dynamics; protein aggregation; α-synuclein