title: A Rational Design Strategy for the Selective Activity Enhancement of a Molecular Chaperone toward a Target Substrate.
abstract: Molecular chaperones facilitate the folding and assembly of proteins and inhibit their aberrant aggregation. They thus offer several opportunities for biomedical and biotechnological applications, as for example they can often prevent protein aggregation more effectively than other therapeutic molecules, including small molecules and antibodies. Here we present a method of designing molecular chaperones with enhanced activity against specific amyloidogenic substrates while leaving unaltered their functions toward other substrates. The method consists of grafting onto a molecular chaperone a peptide designed to bind specifically an epitope in the target substrate. We illustrate this strategy by describing Hsp70 variants with increased affinities for α-synuclein and Aβ42 but otherwise unaltered affinities for other substrates. These designed variants inhibit protein aggregation and disaggregate preformed fibrils significantly more effectively than wild-type Hsp70 indicating that the strategy presented here provides a possible route for tailoring rationally molecular chaperones for specific purposes.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Aprile
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
authors.forename: Pietro
authors.initials: P
authors.lastname: Sormanni
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D015195:Drug Design; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000517:prevention & control; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011994:Recombinant Proteins; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)