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

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...

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Autores principales: Olszewski, Michal M., Williams, Cameron, Dong, Ken C., Martin, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340886/
https://www.ncbi.nlm.nih.gov/pubmed/30675527
http://dx.doi.org/10.1038/s42003-019-0283-z
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author Olszewski, Michal M.
Williams, Cameron
Dong, Ken C.
Martin, Andreas
author_facet Olszewski, Michal M.
Williams, Cameron
Dong, Ken C.
Martin, Andreas
author_sort Olszewski, Michal M.
collection PubMed
description 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.
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spelling pubmed-63408862019-01-23 The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome Olszewski, Michal M. Williams, Cameron Dong, Ken C. Martin, Andreas Commun Biol Article 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. Nature Publishing Group UK 2019-01-21 /pmc/articles/PMC6340886/ /pubmed/30675527 http://dx.doi.org/10.1038/s42003-019-0283-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Olszewski, Michal M.
Williams, Cameron
Dong, Ken C.
Martin, Andreas
The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title_full The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title_fullStr The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title_full_unstemmed The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title_short The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome
title_sort cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26s proteasome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340886/
https://www.ncbi.nlm.nih.gov/pubmed/30675527
http://dx.doi.org/10.1038/s42003-019-0283-z
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