title: Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates.
abstract: Structurally and sequence-wise, the Hsp110s belong to a subfamily of the Hsp70 chaperones. Like the classical Hsp70s, members of the Hsp110 subfamily can bind misfolding polypeptides and hydrolyze ATP. However, they apparently act as a mere subordinate nucleotide exchange factors, regulating the ability of Hsp70 to hydrolyze ATP and convert stable protein aggregates into native proteins. Using stably misfolded and aggregated polypeptides as substrates in optimized in vitro chaperone assays, we show that the human cytosolic Hsp110s (HSPH1 and HSPH2) are bona fide chaperones on their own that collaborate with Hsp40 (DNAJA1 and DNAJB1) to hydrolyze ATP and unfold and thus convert stable misfolded polypeptides into natively refolded proteins. Moreover, equimolar Hsp70 (HSPA1A) and Hsp110 (HSPH1) formed a powerful molecular machinery that optimally reactivated stable luciferase aggregates in an ATP- and DNAJA1-dependent manner, in a disaggregation mechanism whereby the two paralogous chaperones alternatively activate the release of bound unfolded polypeptide substrates from one another, leading to native protein refolding.
authors.affiliation: From the Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland and.
authors.forename: Rayees U H
authors.initials: RUH
authors.lastname: Mattoo
authors.affiliation: From the Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland and; the Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: From the Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland and.
authors.forename: Smriti
authors.initials: S
authors.lastname: Priya
authors.affiliation: From the Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland and.
authors.forename: Andrija
authors.initials: A
authors.lastname: Finka
authors.affiliation: From the Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland and. Electronic address: Pierre.Goloubinoff@unil.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Goloubinoff
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D058849:Protein Refolding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D020836:Protein Structure, Quaternary; D058767:Protein Unfolding / Q000187:drug effects*; D012995:Solubility; D013379:Substrate Specificity / Q000187:drug effects; D013696:Temperature; D014357:Trypsin / Q000494:pharmacology
chemical_list: D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; C121993:HSPA4 protein, human; C097205:HSPH1 protein, human; D010455:Peptides; D000255:Adenosine Triphosphate; D008156:Luciferases; D014357:Trypsin
keywords: ATPases; Heat Shock Protein; Molecular Chaperone; Protein Aggregation; Protein Misfolding