Hsp70 displaces small heat shock proteins from aggregates to initiate protein refolding

Szymon Żwirowski , Agnieszka Kłosowska , Igor Obuchowski , Nadinath B Nillegoda , Artur Piróg , Szymon Ziętkiewicz , Bernd Bukau , Axel Mogk , Krzysztof Liberek

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.
Author Szymon Żwirowski MWB UG i GUMed
Szymon Żwirowski,,
- Intercollegiate Faculty of Biotechnology UG
, Agnieszka Kłosowska KBMiK
Agnieszka Kłosowska,,
- Department of Molecular and Cellular Biology
, Igor Obuchowski MWB UG i GUMed
Igor Obuchowski,,
- Intercollegiate Faculty of Biotechnology UG
, Nadinath B Nillegoda
Nadinath B Nillegoda,,
-
, Artur Piróg KBMiK
Artur Piróg,,
- Department of Molecular and Cellular Biology
, Szymon Ziętkiewicz KBMiK
Szymon Ziętkiewicz,,
- Department of Molecular and Cellular Biology
, Bernd Bukau
Bernd Bukau,,
-
, Axel Mogk
Axel Mogk,,
-
, Krzysztof Liberek KBMiK
Krzysztof Liberek,,
- Department of Molecular and Cellular Biology
Other language title versions
Journal seriesEMBO Journal, ISSN 0261-4189
Issue year2017
Vol36
No6
Pages783-796
Publication size in sheets0.65
Keywords in EnglishHsp100 disaggregase, Hsp70, protein aggregation, protein refolding, sHsps
DOIDOI:10.15252/embj.201593378
URL http://onlinelibrary.wiley.com/doi/10.15252/embj.201593378/epdf
Languageen angielski
Score (nominal)45
ScoreMinisterial score = 45.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 45.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 9.792 (2) - 2016=9.853 (5)
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