Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species.
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Peer-reviewed
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Abstract
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.
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Keywords
Binding, Competitive, HSP70 Heat-Shock Proteins, Humans, Kinetics, Protein Multimerization, Protein Structure, Secondary, Substrate Specificity, alpha-Synuclein
Journal Title
Biochemistry
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Journal ISSN
0006-2960
1520-4995
1520-4995
Volume Title
56
Publisher
American Chemical Society (ACS)
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Sponsorship
European Research Council (337969)
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
BBSRC (BB/J002119/1), European Research Council (337969)