Role of Protein−water Interactions and Electrostatics in α-synuclein Fibril Formation
Document Type
Article
Publication Date
2004
Keywords
Anions, Deformation, Nanofibers, Peptides and Proteins, Salts
Digital Object Identifier (DOI)
https://doi.org/10.1021/bi034938r
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Biochemistry, v. 43, issue 11, p. 3289-3300
Scholar Commons Citation
Munishkina, Larissa A.; Henriquez, Jeremy; Uversky, Vladimir N.; and Fink, Anthony L., "Role of Protein−water Interactions and Electrostatics in α-synuclein Fibril Formation" (2004). Molecular Medicine Faculty Publications. 722.
https://digitalcommons.usf.edu/mme_facpub/722
Comments
Deposition of misfolded α-synuclein is a critical factor in several neurodegenerative disorders. Filamentous α-synuclein is the major component of Lewy bodies and Lewy neurites, the intracellular inclusions in the dopaminergic neurons of the substantia nigra, which are considered the pathological hallmark of Parkinson's disease. We show here that anions induce partial folding of α-synuclein at neutral pH, forming a critical amyloidogenic intermediate, which leads to significant acceleration of the rate of fibrillation. The magnitude of the accelerating effect generally followed the position of the anions in the Hofmeister series, indicating a major role of protein−water−anion interactions in the process at salt concentrations above 10 mM. Below this concentration, electrostatic effects dominated in the mechanism of anion-induced fibrillation. The acceleration of fibrillation by anions was also dependent on the cation. Moderate concentrations of anions affected both the rates of nucleation and the elongation of α-synuclein fibrillation, primarily via their effect on the interaction of the protein with water.