NudC guides client transfer between the Hsp40/70 and Hsp90 chaperone systems

Maximilian M Biebl; Florent Delhommel; Ofrah Faust; Krzysztof M Zak; Ganesh Agam; Xiaoyan Guo; Moritz Mühlhofer; Vinay Dahiya; Daniela Hillebrand; Grzegorz M Popowicz; Martin Kampmann; Don C Lamb; Rina Rosenzweig; Michael Sattler; Johannes Buchner

doi:10.1016/j.molcel.2021.12.031

NudC guides client transfer between the Hsp40/70 and Hsp90 chaperone systems

Mol Cell. 2022 Feb 3;82(3):555-569.e7. doi: 10.1016/j.molcel.2021.12.031. Epub 2022 Jan 20.

Authors

Affiliations

¹ Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
² Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany; Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
³ Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
⁴ Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ Department of Chemistry, Ludwig-Maximilians-Universität München, München, Germany.
⁶ Institute for Neurodegenerative Diseases University of California, San Francisco, CA, USA; Department for Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
⁷ Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany; Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany. Electronic address: sattler@helmholtz-muenchen.de.
⁸ Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany. Electronic address: johannes.buchner@tum.de.

PMID: 35063133
DOI: 10.1016/j.molcel.2021.12.031

Abstract

In the eukaryotic cytosol, the Hsp70 and the Hsp90 chaperone machines work in tandem with the maturation of a diverse array of client proteins. The transfer of nonnative clients between these systems is essential to the chaperoning process, but how it is regulated is still not clear. We discovered that NudC is an essential transfer factor with an unprecedented mode of action: NudC interacts with Hsp40 in Hsp40-Hsp70-client complexes and displaces Hsp70. Then, the interaction of NudC with Hsp90 allows the direct transfer of Hsp40-bound clients to Hsp90 for further processing. Consistent with this mechanism, NudC increases client activation in vitro as well as in cells and is essential for cellular viability. Together, our results show the complexity of the cooperation between the major chaperone machineries in the eukaryotic cytosol.

Keywords: Glucocorticoid receptor; Hsp40; Hsp70; Hsp90; NMR spectroscopy; NudC; co-chaperones; molecular chaperones; protein folding; spFRET.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Survival
HEK293 Cells
HSP40 Heat-Shock Proteins / genetics
HSP40 Heat-Shock Proteins / metabolism*
HSP90 Heat-Shock Proteins / genetics
HSP90 Heat-Shock Proteins / metabolism*
Humans
K562 Cells
Kinetics
Molecular Docking Simulation
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein Binding
Protein Folding
Protein Interaction Domains and Motifs
Receptors, Glucocorticoid / genetics
Receptors, Glucocorticoid / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Cell Cycle Proteins
DNAJB1 protein, human
HSP40 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
NUDC protein, human
Nuclear Proteins
Receptors, Glucocorticoid
TP53 protein, human
Tumor Suppressor Protein p53

Grants and funding

DP2 GM119139/GM/NIGMS NIH HHS/United States