Breaking the chains: structure and function of the deubiquitinases

• Published in: Nature reviews. Molecular cell biology Vol. 10; no. 8; pp. 550 - 563
• Main Authors: Komander, David, Clague, Michael J., Urbé, Sylvie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2009; Nature Publishing Group
• Subjects: Animals; Biocatalysis; Biochemistry; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cellular signal transduction; Developmental Biology; Endopeptidases - chemistry; Endopeptidases - metabolism; Enzymes; Genetic aspects; Humans; Life Sciences; Physiological aspects; Post-translational modification; Proteins; review-article; Signal transduction; Stem Cells; Structure; Substrate Specificity; Ubiquitin-proteasome system; Zinc; United Kingdom; United Kingdom > UK
• ISSN: 1471-0072; 1471-0080; 1471-0080
• DOI: 10.1038/nrm2731

Key Points Ubiquitylation is a reversible post-translational modification involved in a myriad of cellular functions. A superfamily of approximately 100 ubiquitin-specific proteases, called deubiquitylating enzymes, deubiquitinases or DUBs, remove ubiquitin from target proteins, disassemble polymeric ubiquitin chains and process ubiquitin precursor polypeptides to maintain ubiquitin homeostasis in cells. Most DUBs are Cys proteases; a small group are metalloproteases. DUBs are classified into five families (ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Ovarian tumour proteases (OTUs), Josephins and JAB1/MPN/Mov34 metalloenzymes (JAMMs, also known as MPN+) that are structurally unrelated, but all interact with a common hydrophobic patch on ubiquitin. Multiple layers of regulation modulate the activity and specificity of these enzymes. Specificity also entails recognition of and selective activity towards particular ubiquitin chain types, at least eight of which are now known to coexist in yeast and mammalian cells. DUBs might function to regulate both the stability and the activity of target proteins, which include oncogenes and tumour suppressors. Their wide-ranging involvement in key regulatory processes makes DUBs attractive targets for drug therapy. A large superfamily of deubiquitinases (DUBs) has a key role in both determining protein stability and terminating ubiquitin-dependent signal transduction. Structural and biochemical studies have started to reveal the underlying principles by which DUB substrate specificity is achieved. Ubiquitylation is a reversible protein modification that is implicated in many cellular functions. Recently, much progress has been made in the characterization of a superfamily of isopeptidases that remove ubiquitin: the deubiquitinases (DUBs; also known as deubiquitylating or deubiquitinating enzymes). Far from being uniform in structure and function, these enzymes display a myriad of distinct mechanistic features. The small number (<100) of DUBs might at first suggest a low degree of selectivity; however, DUBs are subject to multiple layers of regulation that modulate both their activity and their specificity. Due to their wide-ranging involvement in key regulatory processes, these enzymes might provide new therapeutic targets.