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Commun Biol. 2019 Jan 21;2(1):29. doi: 10.1038/s42003-019-0283-z.

The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome.

Olszewski MM1,2, Williams C1,2,3, Dong KC1,2,4, Martin A5,6,7.

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA.
2
California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA.
3
Biophysics Graduate Group, University of California, Berkeley, CA, 94720, USA.
4
Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA.
5
Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.
6
California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.
7
Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA. a.martin@berkeley.edu.

Abstract

Cdc48/p97 is an essential and highly conserved AAA+ ATPase that uses its protein-unfoldase activity to extract ubiquitinated polypeptides from macromolecular complexes and membranes. This motor has also been implicated in protein-degradation pathways, yet its exact role in acting upstream of the 26S proteasome remains elusive. Ubiquitinated proteins destined for degradation by the proteasome require an unstructured initiation region to engage with the proteasomal translocation machinery, and Cdc48 was proposed to generate these unfolded segments, yet direct evidence has been missing. Here, we used an in vitro reconstituted system to demonstrate the collaboration of Cdc48 and the 26S proteasome from S. cerevisiae in degrading ubiquitinated, well-folded proteins that lack unstructured segments. Our data indicate that a critical role for Cdc48 in the ubiquitin-proteasome system is to create flexible initiation regions in compact substrates that otherwise would be refractory to engagement and degradation by the proteasome.

PMID:
31924914
DOI:
10.1038/s42003-019-0283-z

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