title: Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species.
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.
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Francesco A
authors.identifier: 0000-0002-5040-4420
authors.initials: FA
authors.lastname: Aprile
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich , Vladimir-Prelog-Weg 1, 8093 Zurich, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Fusco
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Serene W
authors.initials: SW
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Kumita
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Dhulesia
authors.affiliation: Department of Biotechnology and Bioscience, University of Milano-Bicocca , Piazza della Scienza 2, 20126 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortora
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza , 50018 Zaragoza, Spain.
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
mesh_terms: D001667:Binding, Competitive; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein