title: Experimental Milestones in the Discovery of Molecular Chaperones as Polypeptide Unfolding Enzymes.
abstract: Molecular chaperones control the cellular folding, assembly, unfolding, disassembly, translocation, activation, inactivation, disaggregation, and degradation of proteins. In 1989, groundbreaking experiments demonstrated that a purified chaperone can bind and prevent the aggregation of artificially unfolded polypeptides and use ATP to dissociate and convert them into native proteins. A decade later, other chaperones were shown to use ATP hydrolysis to unfold and solubilize stable protein aggregates, leading to their native refolding. Presently, the main conserved chaperone families Hsp70, Hsp104, Hsp90, Hsp60, and small heat-shock proteins (sHsps) apparently act as unfolding nanomachines capable of converting functional alternatively folded or toxic misfolded polypeptides into harmless protease-degradable or biologically active native proteins. Being unfoldases, the chaperones can proofread three-dimensional protein structures and thus control protein quality in the cell. Understanding the mechanisms of the cellular unfoldases is central to the design of new therapies against aging, degenerative protein conformational diseases, and specific cancers.
authors.affiliation: Laboratory of Biophysical Statistics, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Andrija
authors.initials: A
authors.lastname: Finka
authors.affiliation: Department of Structural Biology, Stanford University, Stanford, California 94305; email: rmattoo@stanford.edu.
authors.forename: Rayees U H
authors.initials: RU
authors.lastname: Mattoo
authors.affiliation: Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland; email: pierre.goloubinoff@unil.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Goloubinoff
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D018834:Chaperonin 60 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D050957:HSP110 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D066329:Protein Aggregates; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D058767:Protein Unfolding; D012247:Rhodospirillum rubrum / Q000737:chemistry / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C060293:HSPD1 protein, human; C097205:HSPH1 protein, human; D050888:Heat-Shock Proteins, Small; D024101:Mitochondrial Proteins; D066329:Protein Aggregates; D000255:Adenosine Triphosphate
keywords: Hsp104; Hsp110; Hsp60; Hsp70; heat-shock proteins; protein homeostasis; sHsps; small heat-shock proteins; unfoldases