文章基本信息

标题：DUB esterase activity further decodes ubiquitin’s enigma
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作者：Benedikt M. Kessler
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：6
页码：1
DOI：10.1073/pnas.2026389118
出版社：The National Academy of Sciences of the United States of America
摘要：Posttranslational modifications of proteins are often key to understanding their biological function, localization, and fate. In particular, the covalent attachment of ubiquitin, a small 76-amino acid polypeptide, to substrates has attracted recent attention and is being exploited to generate novel drugs capable of removing pathogenic targets in a selective fashion (proteolysis-targeting chimeras) (1). Conjugation of ubiquitin can be reversed by deubiquitinating enzymes (DUBs), reflecting additional regulation (2). Control for reversing protein ubiquitylation has been the subject of Satpal Virdee and coworkers (3), who have developed a DUB amino acid profiling assay that led to the discovery of a class of ubiquitin esterases, classically assigned as ubiquitin specific proteases. As reported in PNAS, the authors show, for a subset of DUBs from the Machado−Josephin Domain (MJD) family, previously with unknown function, their ability to cleave ubiquitin not only from lysine-based “classical” isopeptide bonds but also from ubiquitin moieties linked to serine and threonine side chains via ester linkages (3). Protein ubiquitination seems predominantly restricted to the attachment of ubiquitin C termini to lysine (Lys) residues, forming “classical” isopeptide and, in the case of linear ubiquitin chains, peptide bonds (Fig. 1 A ). This is, in part, due to the unique length of the hydrocarbon chain of Lys that appears to be most optimal for E2/E3 enzymes’ reaction and transition of ubiquitin molecules to substrates (4). At the same time, there has been a precedence for ubiquitin covalent linkages other than to lysine epsilon amine side chains representing “canonical ubiquitylation.” For instance, in the context of ubiquitin conjugation.