title: Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding.
abstract: Small heat shock proteins (sHsps) are an evolutionary conserved class of ATP-independent chaperones that protect cells against proteotoxic stress. sHsps form assemblies with aggregation-prone misfolded proteins, which facilitates subsequent substrate solubilization and refolding by ATP-dependent Hsp70 and Hsp100 chaperones. Substrate solubilization requires disruption of sHsp association with trapped misfolded proteins. Here, we unravel a specific interplay between Hsp70 and sHsps at the initial step of the solubilization process. We show that Hsp70 displaces surface-bound sHsps from sHsp-substrate assemblies. This Hsp70 activity is unique among chaperones and highly sensitive to alterations in Hsp70 concentrations. The Hsp70 activity is reflected in the organization of sHsp-substrate assemblies, including an outer dynamic sHsp shell that is removed by Hsp70 and a stable core comprised mainly of aggregated substrates. Binding of Hsp70 to the sHsp/substrate core protects the core from aggregation and directs sequestered substrates towards refolding pathway. The sHsp/Hsp70 interplay has major impact on protein homeostasis as it sensitizes substrate release towards cellular Hsp70 availability ensuring efficient refolding of damaged proteins under favourable folding conditions.
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Żwirowski
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kłosowska
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland.
authors.forename: Igor
authors.initials: I
authors.lastname: Obuchowski
authors.affiliation: Center for Molecular Biology, University of Heidelberg (ZMBH), Heidelberg, Germany.|German Cancer Research Centre (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Nadinath B
authors.initials: NB
authors.lastname: Nillegoda
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Piróg
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Ziętkiewicz
authors.affiliation: Center for Molecular Biology, University of Heidelberg (ZMBH), Heidelberg, Germany.|German Cancer Research Centre (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
authors.affiliation: Center for Molecular Biology, University of Heidelberg (ZMBH), Heidelberg, Germany.|German Cancer Research Centre (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Mogk
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, University of Gdansk, Gdansk, Poland krzysztof.liberek@biotech.ug.edu.pl.
authors.forename: Krzysztof
authors.identifier: 0000-0002-7532-9279
authors.initials: K
authors.lastname: Liberek
mesh_terms: D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D066329:Protein Aggregates; D058849:Protein Refolding
chemical_list: D018840:HSP70 Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D066329:Protein Aggregates
keywords: Hsp100 disaggregase; Hsp70; protein aggregation; protein refolding; sHsps