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Mol Cell. 2018 Nov 15;72(4):766-777.e6. doi: 10.1016/j.molcel.2018.09.020. Epub 2018 Oct 18.

Ubiquitin-Independent Disassembly by a p97 AAA-ATPase Complex Drives PP1 Holoenzyme Formation.

Author information

1
Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45117 Essen, Germany.
2
Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45117 Essen, Germany; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
3
Laboratory of Biosignaling and Therapeutics, KU Leuven, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium.
4
Analytics Core Facility, Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45117 Essen, Germany.
5
Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45117 Essen, Germany. Electronic address: hemmo.meyer@uni-due.de.

Abstract

The functional diversity of protein phosphatase-1 (PP1), with its countless substrates, relies on the ordered assembly of alternative PP1 holoenzymes. Here, we show that newly synthesized PP1 is first held by its partners SDS22 and inhibitor-3 (I3) in an inactive complex, which needs to be disassembled by the p97 AAA-ATPase to promote exchange to substrate specifiers. Unlike p97-mediated degradative processes that require the Ufd1-Npl4 ubiquitin adapters, p97 is targeted to PP1 by p37 and related adapter proteins. Reconstitution with purified components revealed direct interaction of the p37 SEP domain with I3 without the need for ubiquitination, and ATP-driven pulling of I3 into the central channel of the p97 hexamer, which triggers dissociation of I3 and SDS22. Thus, we establish regulatory ubiquitin-independent protein complex disassembly as part of the functional arsenal of p97 and define an unanticipated essential step in PP1 biogenesis that illustrates the molecular challenges of ordered subunit exchange.

KEYWORDS:

AAA ATPase; VCP/p97; protein biogenesis; protein phosphatase-1; protein unfolding; ubiquitin

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PMID:
30344098
DOI:
10.1016/j.molcel.2018.09.020
[Indexed for MEDLINE]

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