The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange

Ubiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-β response, NF-κB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its...

Full description

Bibliographic Details
Main Authors:	Clerici, Marcello, Luna-Vargas, Mark P. A., Faesen, Alex C., Sixma, Titia K.
Format:	Online
Language:	English
Published:	Nature Pub. Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243247/

id	pubmed-4243247
recordtype	oai_dc
spelling	pubmed-42432472014-12-05 The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange Clerici, Marcello Luna-Vargas, Mark P. A. Faesen, Alex C. Sixma, Titia K. Article Ubiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-β response, NF-κB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its N-terminal DUSP–Ubl domain to achieve full catalytic turnover. Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis. The DUSP–Ubl domain is able to enhance ubiquitin dissociation, hence promoting efficient turnover. In a mechanism that requires all USP4 domains, binding of the DUSP–Ubl domain promotes a change of a switching loop near the active site. This ‘allosteric regulation of product discharge’ provides a novel way of regulating deubiquitinating enzymes that may have relevance for other enzyme classes. Nature Pub. Group 2014-11-18 /pmc/articles/PMC4243247/ /pubmed/25404403 http://dx.doi.org/10.1038/ncomms6399 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Clerici, Marcello Luna-Vargas, Mark P. A. Faesen, Alex C. Sixma, Titia K.
spellingShingle	Clerici, Marcello Luna-Vargas, Mark P. A. Faesen, Alex C. Sixma, Titia K. The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
author_facet	Clerici, Marcello Luna-Vargas, Mark P. A. Faesen, Alex C. Sixma, Titia K.
author_sort	Clerici, Marcello
title	The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
title_short	The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
title_full	The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
title_fullStr	The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
title_full_unstemmed	The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
title_sort	dusp–ubl domain of usp4 enhances its catalytic efficiency by promoting ubiquitin exchange
description	Ubiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-β response, NF-κB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its N-terminal DUSP–Ubl domain to achieve full catalytic turnover. Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis. The DUSP–Ubl domain is able to enhance ubiquitin dissociation, hence promoting efficient turnover. In a mechanism that requires all USP4 domains, binding of the DUSP–Ubl domain promotes a change of a switching loop near the active site. This ‘allosteric regulation of product discharge’ provides a novel way of regulating deubiquitinating enzymes that may have relevance for other enzyme classes.
publisher	Nature Pub. Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243247/
_version_	1613160501508833280

The DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange

Similar Items