Breaking the chains: structure and function of the deubiquitinases

Abstract

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.

Deubiquitinases in cancer: new functions and therapeutic options

“…Conversely, ubiquitin removal is catalyzed by DUBs, which specifically cleave the isopeptide bond between the e-amino group of lysine side chains of target proteins and the Cterminal group of ubiquitin, or the peptidic bond between the a-amino group of the target protein and the Cterminal group of ubiquitin (Wilkinson, 1997). The human genome encodes at least 98 DUBs subdivided into 6 families based on sequence and structural similarity: ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), ovarian-tumor proteases (OTUs), Machado-Joseph disease protein domain proteases, JAMM/MPN domain-associated metallopeptidases (JAMMs) and the recently discovered monocyte chemotactic protein-induced protein (MCPIP) family (Reyes-Turcu et al, 2009;Komander et al, 2009a;Liang et al, 2010). All of them are cysteine proteases with the exception of JAMMs, which belong to the catalytic class of metalloproteases (Figure 1, Supplementary Table 1 and http://degradome.uniovi.es).…”

“…Furthermore, many USPs exhibit additional domains and terminal extensions that have important roles in their activity and specificity. These domains include the B-box domain found in CYLD, the zinc-finger USP domain shared by USP3, USP5, USP39, USP44, USP45, USP49 and USP51, the ubiquitin-interacting motif located in USP25 and USP37, the ubiquitin-associated domain in USP5 and USP13, the domain in USPs (DUSP) present in USP4, USP11, USP15, USP20, USP33 and USP48, the exonuclease III domain found in USP52, as well as the ubiquitin-like domain that can be located both within and outside the catalytic domains of several USPs, such as USP4, USP7, USP14, USP32, USP47 and USP48 (Quesada et al, 2004;Zhu et al, 2007b;Komander et al, 2009a) (Figure 1). Despite their relative structural diversity, most USPs share the common feature of undergoing conformational changes upon ubiquitin binding, which drives the transition from an inactive form to a catalytically active state.…”

“…Most of them cleave a-peptide bonds between naturally occurring amino acids, but there are some degradome members that perform slightly different chemical reactions. Among them, a large and growing group of proteases known as DUBs (deubiquitylating enzymes or deubiquitinases) have emerged as pivotal regulators of ubiquitinmediated signaling pathways, because of their capacity to hydrolyze isopeptide bonds in ubiquitin protein conjugates (Reyes-Turcu et al, 2009;Komander et al, 2009a). After a brief introduction to the structural and enzymatic diversity of human DUBs and their regulatory mechanisms, this review will focus on the description of the functional complexity of these enzymes in tumor development and progression.…”

Protein monoubiquitylation: targets and diverse functions

“…Ubiquitin is synthesized as an inactive precursor protein from four distinct genes ( UBA52 , UBA80 , UBB , UBC ), and the precursor is then cleaved by a deubiquitinase (DUB) enzyme to yield ubiquitin with active diglycine residues exposed at its COOH‐terminus (Komander et al . 2009) (Fig. 1).…”

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

“…Ubiquitination is a reversible modification, important for termination of signalling events, editing of Ub-protein modifications and recycling of Ub [6]. Deubiquitination is catalysed by a large family of over 80 different deubiquitinases (DUBs), which can be subdivided into five distinct super-families, the ubiquitin specific proteases (USPs), the ubiquitin C-terminal hydrolases (UCHs), the Machado-Josephin domain proteases (MJDs), the ovarian tumour proteases (OTU) and the JAB1/MPN/Mov34 (JAMM) domain metalloproteinases [7]. DUB specificity is also determined by cellular location, specific binding interactions and the type of ubiquitin chain linkage and removal of these ubiquitin adducts regulates either the proteins stability or its activity [8].…”