Summary table of USP15 transcripts.

All USP15 isoforms encompass a single N-terminal DUSP (domain in USPs) characterised by a novel tripod-like fold with a conserved hydrophobic surface patch that is predicted to participate in protein-protein interaction (de Jong et al., 2006). The ubiquitin carboxyl-terminal hydrolase (UCH) catalytic core of the USPs is typically around 350 amino acids, but consists of six conserved boxes, interspersed by insertion sites for additional sequence that can confer diversity (Ye et al., 2009). The major insertion in USP15 is between boxes 3/4, and embeds an ubiquitin-like fold (UBL) domain within the catalytic domain. UBLs are commonly found in the USPs and in certain other DUB families (Zhu et al., 2007; Komander et al., 2009a). They exhibit low sequence conservation, but have high structural similarity with ubiquitin and have been proposed to play important roles in regulating DUB catalytic function or interactions (Zhu et al., 2007; Ye et al., 2009). The intercalation of a UBL between boxes 3 and 4 of the catalytic domain increases the spacing between two sets of zinc-coordinating cysteine motifs, which form a functional zinc finger that is required for activity (Hetfeld et al., 2005). In the case of USP15, a second UBL is located directly adjacent to the DUSP (Zhu et al., 2007; Ye et al., 2009).
The four USP15 splice variants encode four distinct protein isoforms, which are illustrated in the diagram and summarised in the accompanying table. As a consequence of alternative splicing, isoform USP15-201 has a 29 amino acid insert within the unstructured region between the first UBL domain and the start of the UCH domain, whereas USP15-204 has a substitution of 3 amino acids for 8 residues within the first UBL. Otherwise the three isoforms that retain the catalytic domain are identical. They also retain predicted nuclear export signals (NES) (Soboleva et al., 2005) and, by homology with rat, a functional nuclear localisation signal (NLS) (Park et al., 2000).