The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2

Abstract Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular...

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Autores principales:	Yung-Cheng Shin, Jou-Han Chen, Shih-Chung Chang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1c12c4f9e05644f68d5119d47b21028a
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spelling	oai:doaj.org-article:1c12c4f9e05644f68d5119d47b21028a2021-12-02T12:32:40ZThe molecular determinants for distinguishing between ubiquitin and NEDD8 by USP210.1038/s41598-017-02322-x2045-2322https://doaj.org/article/1c12c4f9e05644f68d5119d47b21028a2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02322-xhttps://doaj.org/toc/2045-2322Abstract Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular determinants for distinguishing between Ub and NEDD8 by Ub-specific peptidases (USPs) remain poorly characterized. By replacing the non-conserved residues of Ub with their NEDD8 equivalents by mutagenesis, and vice versa, we observed that the Ub4K, Ub12E, and Ub14E mutants partially and the Ub4K/12E/14E/72A mutant completely prevented their hydrolysis by USP2. The NEDD84F and NEDD814T mutants were slightly hydrolyzed by USP2; however, the NEDD812T/14T/72R and NEDD84F/12T/14T/72R mutants were accessible for hydrolysis by USP2, suggesting that Ub and NEDD8 residues 4, 12, 14, and 72 serve as the molecular determinants for specific recognition by USP2. We also demonstrated that the level of inhibition caused by Ub mutants with multiple mutation sites was not purely additive when compared with the single mutation results. Furthermore, USP2 was determined to bind to the N-terminus of Ub to form a stable interaction, after which it binds with the C-terminus of Ub to ensure substrate specificity. The same results were also discovered when Ub, Ub4K/12E/14E/72A, NEDD8, and NEDD84F/12T/14T/72R were incubated with USP21.Yung-Cheng ShinJou-Han ChenShih-Chung ChangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yung-Cheng Shin Jou-Han Chen Shih-Chung Chang The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
description	Abstract Ubiquitin (Ub) shares the highest sequence identity with neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8) in the Ub-like protein family. However, different enzyme systems are precisely employed for targeting Ub and NEDD8 to specific substrates. The molecular determinants for distinguishing between Ub and NEDD8 by Ub-specific peptidases (USPs) remain poorly characterized. By replacing the non-conserved residues of Ub with their NEDD8 equivalents by mutagenesis, and vice versa, we observed that the Ub4K, Ub12E, and Ub14E mutants partially and the Ub4K/12E/14E/72A mutant completely prevented their hydrolysis by USP2. The NEDD84F and NEDD814T mutants were slightly hydrolyzed by USP2; however, the NEDD812T/14T/72R and NEDD84F/12T/14T/72R mutants were accessible for hydrolysis by USP2, suggesting that Ub and NEDD8 residues 4, 12, 14, and 72 serve as the molecular determinants for specific recognition by USP2. We also demonstrated that the level of inhibition caused by Ub mutants with multiple mutation sites was not purely additive when compared with the single mutation results. Furthermore, USP2 was determined to bind to the N-terminus of Ub to form a stable interaction, after which it binds with the C-terminus of Ub to ensure substrate specificity. The same results were also discovered when Ub, Ub4K/12E/14E/72A, NEDD8, and NEDD84F/12T/14T/72R were incubated with USP21.
format	article
author	Yung-Cheng Shin Jou-Han Chen Shih-Chung Chang
author_facet	Yung-Cheng Shin Jou-Han Chen Shih-Chung Chang
author_sort	Yung-Cheng Shin
title	The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
title_short	The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
title_full	The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
title_fullStr	The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
title_full_unstemmed	The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2
title_sort	molecular determinants for distinguishing between ubiquitin and nedd8 by usp2
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1c12c4f9e05644f68d5119d47b21028a
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The molecular determinants for distinguishing between ubiquitin and NEDD8 by USP2

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