Also known as: His₆-USP8 (UBPY)

USP8 (Ubiquitin Specific Protease8) is a growth-regulated deubiquitinating enzyme (DUB) with a role in endosomal sorting of receptor tyrosine kinases (RTKs) such as EGFR in vivo USP8 is a complex protein with a coiled-coil region, non-classical SH3 binding motif, rhodanese and catalytic domains whose individual structures have been determined. The N-terminus has a novel dimerization fold but it is not known if the full-length protein exists as a homodimer. The C-terminus contains the DUB catalytic center and a nearby Zn⁺⁺ ribbon subdomain which might have a role in poly-Ub binding specificity and substrate-induced conformational changes. USP8 has DUB activity on Ub chains in vitro and does not discriminate between K48- and K63-linked isopeptide bonds. USP8 interacts with several proteins including Hrs binding protein Hbp, Mona/Gads, Ras exchange factor CDC25Mm, GRAIL3 and NRDP1 E3 ligases, and 14-3-3ε. The overall function of USP8 is still unclear but its main role is in endocytosis which influences signaling cascades for mitogenesis, cell survival, differentiation and migration. This protein contains an N-terminal His₆-tag.