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Ubiquitin chain conformation regulates recognition and activity of interacting proteins

Mechanisms of protein recognition have been extensively studied for single-domain proteins(1), but are less well characterized for dynamic multi-domain systems. Ubiquitin (Ub) chains represent a biologically important multi-domain system that requires recognition by structurally diverse Ub-interacti...

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Autores principales: Ye, Yu, Blaser, Georg, Horrocks, Mathew H., Ruedas-Rama, Maria J., Ibrahim, Shehu, Zhukov, Alexander A., Orte, Angel, Klenerman, David, Jackson, Sophie E., Komander, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605796/
https://www.ncbi.nlm.nih.gov/pubmed/23201676
http://dx.doi.org/10.1038/nature11722
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author Ye, Yu
Blaser, Georg
Horrocks, Mathew H.
Ruedas-Rama, Maria J.
Ibrahim, Shehu
Zhukov, Alexander A.
Orte, Angel
Klenerman, David
Jackson, Sophie E.
Komander, David
author_facet Ye, Yu
Blaser, Georg
Horrocks, Mathew H.
Ruedas-Rama, Maria J.
Ibrahim, Shehu
Zhukov, Alexander A.
Orte, Angel
Klenerman, David
Jackson, Sophie E.
Komander, David
author_sort Ye, Yu
collection PubMed
description Mechanisms of protein recognition have been extensively studied for single-domain proteins(1), but are less well characterized for dynamic multi-domain systems. Ubiquitin (Ub) chains represent a biologically important multi-domain system that requires recognition by structurally diverse Ub-interacting proteins (UbIPs)(2,3). Ub chain conformations in isolation are often different from conformations observed in UbIP complexes, suggesting either great dynamic flexibility or extensive chain remodeling upon binding. Using single-molecule FRET, we show here that Lys63-, Lys48- and Met1-linked diUb exist in several distinct conformational states in solution. Lys63- and Met1-linked diUb adopt extended ‘open’ and more compact ‘closed’ conformations, and Ub binding domains (UBDs) and deubiquitinases (DUBs) select pre-existing conformations. In contrast, Lys48-linked diUb adopts predominantly compact conformations. DUBs directly recognize existing conformations, but may also remodel Ub chains to hydrolyze the isopeptide bond. Disruption of the Lys48-diUb interface changes conformational dynamics and affects DUB activity. Hence, conformational equilibria in Ub chains provide an additional layer of regulation in the Ub system, and distinct conformations observed in differently linked polyUb may contribute to the specificity of UbIPs.
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spelling pubmed-36057962013-06-13 Ubiquitin chain conformation regulates recognition and activity of interacting proteins Ye, Yu Blaser, Georg Horrocks, Mathew H. Ruedas-Rama, Maria J. Ibrahim, Shehu Zhukov, Alexander A. Orte, Angel Klenerman, David Jackson, Sophie E. Komander, David Nature Article Mechanisms of protein recognition have been extensively studied for single-domain proteins(1), but are less well characterized for dynamic multi-domain systems. Ubiquitin (Ub) chains represent a biologically important multi-domain system that requires recognition by structurally diverse Ub-interacting proteins (UbIPs)(2,3). Ub chain conformations in isolation are often different from conformations observed in UbIP complexes, suggesting either great dynamic flexibility or extensive chain remodeling upon binding. Using single-molecule FRET, we show here that Lys63-, Lys48- and Met1-linked diUb exist in several distinct conformational states in solution. Lys63- and Met1-linked diUb adopt extended ‘open’ and more compact ‘closed’ conformations, and Ub binding domains (UBDs) and deubiquitinases (DUBs) select pre-existing conformations. In contrast, Lys48-linked diUb adopts predominantly compact conformations. DUBs directly recognize existing conformations, but may also remodel Ub chains to hydrolyze the isopeptide bond. Disruption of the Lys48-diUb interface changes conformational dynamics and affects DUB activity. Hence, conformational equilibria in Ub chains provide an additional layer of regulation in the Ub system, and distinct conformations observed in differently linked polyUb may contribute to the specificity of UbIPs. 2012-12-02 2012-12-13 /pmc/articles/PMC3605796/ /pubmed/23201676 http://dx.doi.org/10.1038/nature11722 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ye, Yu
Blaser, Georg
Horrocks, Mathew H.
Ruedas-Rama, Maria J.
Ibrahim, Shehu
Zhukov, Alexander A.
Orte, Angel
Klenerman, David
Jackson, Sophie E.
Komander, David
Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title_full Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title_fullStr Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title_full_unstemmed Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title_short Ubiquitin chain conformation regulates recognition and activity of interacting proteins
title_sort ubiquitin chain conformation regulates recognition and activity of interacting proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605796/
https://www.ncbi.nlm.nih.gov/pubmed/23201676
http://dx.doi.org/10.1038/nature11722
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