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Nature. 2015 Aug 13;524(7564):247-51. doi: 10.1038/nature14884. Epub 2015 Aug 5.

Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation.

Author information

1
Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
2
Leibniz-Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany.
3
Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany.
4
1] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [2] Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, Heidelberg University, 69120 Heidelberg, Germany.
5
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland.
6
1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, 8057 Zurich, Switzerland.
7
1] Center for Molecular Biology of the University of Heidelberg (ZMBH), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany [2] Heidelberg Institute for Theoretical Studies (HITS), 69118 Heidelberg, Germany [3] Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany.
8
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.

Abstract

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.

PMID:
26245380
PMCID:
PMC4830470
DOI:
10.1038/nature14884
[Indexed for MEDLINE]
Free PMC Article

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