Substrate specificity of the ubiquitin and Ubl proteases

Abstract

Conjugation and deconjugation of ubiquitin and ubiquitin-like proteins (Ubls) to cellular proteins are highly regulated processes integral to cellular homeostasis. Most often, the C-termini of these small polypeptides are attached to lysine side chains of target proteins by an amide (isopeptide) linkage. Deubiquitinating enzymes (DUBs) and Ubl-specific proteases (ULPs) comprise a diverse group of proteases that recognize and remove ubiquitin and Ubls from their substrates. How DUBs and ULPs distinguish among different modifiers, or different polymeric forms of these modifiers, remains poorly understood. The specificity of ubiquitin/Ubl-deconjugating enzymes for particular substrates depends on multiple factors, ranging from the topography of specific substrate features, as in different polyubiquitin chain types, to structural elements unique to each enzyme. Here we summarize recent structural and biochemical studies that provide insights into mechanisms of substrate specificity among various DUBs and ULPs. We also discuss the unexpected specificities of non-eukaryotic proteases in these families.

Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis

“…Both features are conserved in NEDD8, but not in other Ubls such as SMT3 [12] . Other conserved residues in NEDD8 include Arg42, Gln49, His68, Val70 and Arg74 (Figure 5C) – all of which are also present in ubiquitin and are important for the Cdu1-Ub interaction.…”

Proteasome Structure and Assembly

“…An insertion sequence in Rpn11, Ins-2, helps ensure the proper positioning of Rpn11 over the ATPase channel via interactions with the base subunit Rpn2[131]. In other DUBs, the Ins-2 segment is important for maintaining enzyme structural integrity [143]. High-resolution structural analyses have clarified additional details regarding the mechanism of Rpn11 action and its inhibition when not incorporated into proteasomes[125,131].…”

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

“…The human genome encodes approximately 100 potential DUBs which can be classified into six families: ubiquitin-specific proteases (USPs), ubiquitin COOH-terminal hydrolases (UCHs), ovarian tumor proteases (OTUs), Josephins, the JAB1/MPN/MOV34 family (JAMMs) and motif interacting with Ub-containing novel DUB family (MINDYs) (Abdul Rehman et al, 2016). USPs, UCHs, OTUs, Josephins and the newly identified MINDYs families are thiol proteases, while the sixth family, JAMMs, comprises zinc metalloproteases (Ronau, Beckmann, & Hochstrasser, 2016). …”