The Deubiquitylating enzymes (DUBs) regulate ubiquitin dependent signaling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like protein (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB, cysteine proteases and metalloproteases. Ubiquitin specific processing protease 5 (USP5) is a member of the cysteine protease enzyme family and cloning of the human gene was first described by Wilkinson et al. (1995). USP5 protein contains an N-terminal zinc finger ubiquitin-binding domain (ZNF-UBP), a ubiquitin-specific processing protease (UBP) domain containing the active-site cys and his boxes, and two ubiquitin-associated domains (UBA1 and UBA2) (Reyes-Turcu et al., 2006). Crystal structures of the ZNF-UBP domain have revealed a deep binding pocket where the C-terminal diglycine motif of ubiquitin is inserted explaining the specificity of USP for an unmodified C-terminus on the proximal subunit of polyubiquitin (Reyes-Turcu et al., 2006). Recently USP5 has been identified in association with the 26S proteasome alongside other proteins known in complex as the UBL interactome (Besche et al., 2009).
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