Inhibition of α‑Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α‑Synuclein Species

The Hsp70 family of chaperones plays an essential role in suppressing protein aggregation in the cell. Here we investigate the factors controlling the intrinsic ability of human Hsp70 to inhibit the elongation of amyloid fibrils formed by the Parkinson’s disease-related protein α-synuclein. Using ki...

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Bibliographic Details
Published in:Biochemistry (Easton) 2017-03, Vol.56 (9), p.1177-1180
Main Authors: Aprile, Francesco A, Arosio, Paolo, Fusco, Giuliana, Chen, Serene W, Kumita, Janet R, Dhulesia, Anne, Tortora, Paolo, Knowles, Tuomas P. J, Vendruscolo, Michele, Dobson, Christopher M, Cremades, Nunilo
Format: Article
Language:English
Subjects:
alpha-Synuclein - chemistry
alpha-Synuclein - metabolism
Binding, Competitive
HSP70 Heat-Shock Proteins - metabolism
Humans
Kinetics
Protein Multimerization
Protein Structure, Secondary
Substrate Specificity
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Summary:The Hsp70 family of chaperones plays an essential role in suppressing protein aggregation in the cell. Here we investigate the factors controlling the intrinsic ability of human Hsp70 to inhibit the elongation of amyloid fibrils formed by the Parkinson’s disease-related protein α-synuclein. Using kinetic analysis, we show that Hsp70 binds preferentially to α-synuclein fibrils as a consequence of variations in the association and dissociation rate constants of binding to the different aggregated states of the protein. Our findings illustrate the importance of the kinetics of binding of molecular chaperones, and also of potential therapeutic molecules, in the efficient suppression of specific pathogenic events linked to neurodegeneration.
ISSN:0006-2960
1520-4995
DOI:10.1021/acs.biochem.6b01178