Rabbit Isopeptidase T/USP5 Protein, CF

Isopeptidase T/Ubiquitin Specific Peptidase 5 (USP5) is a widely expressed deubiquitinating enzyme belonging to the peptidase C19 family (1). It is the only known member that requires zinc binding to be active (2). It has a predicted molecular weight of 95.8 kDa (3). Human Isopeptidase T/USP5 is 858 amino acids (aa) in length and shares 98% aa sequence identity with the mouse and rat orthologs (3). Isopeptidase T/USP5 is largely responsible for the disassembly of unanchored poly-Ubiquitin chains. It binds multiple Ubiquitin molecules in a poly-Ubiquitin chain and can cleave Lys29-, Lys48- and Lys63-linked chains (1,4,5). It contains four putative Ubiquitin-binding domains: an N-terminal zinc finger Ubiquitin-binding (ZnF-UBP) domain, a Ubiquitin-specific processing protease (UBP) catalytic domain, and two Ubiquitin-associated domains (UBA1 and UBA2) (5-7). The ZnF-UBP domain (aa 163-291) selectively interacts with an unmodified C-terminus of poly-Ubiquitin chains and induces a conformational change that prevents Isopeptidase T/USP5 from disassembling poly-Ubiquitin until another deubiquitinating enzyme has released the chain from the ubiquitinated protein (5,6,8). The UBP domain binds the second Ubiquitin in poly-Ubiquitin, while the subsequent Ubiquitins bind the UBA2 (aa 722-762) and UBA1 (aa 654-695) domains (5,7). There are short and long forms of human Isopeptidase T/USP5 that differ by an insertion of 23 aa in the long form (2). Suppression of Isopeptidase T/USP5 has been shown to increase the amount and transcriptional activity of p53 due to the accumulation of unanchored poly-Ubiquitin (9). Conversely, an up-regulation of USP5 has been associated with fetal Down syndrome (10).