Solution structure of the human ubiquitin-specific protease 15 DUSP domain

Ubiquitin-specific proteases ( USPs) can remove covalently attached ubiquitin moieties from target proteins and regulate both the stability and ubiquitin-signaling state of their substrates. All USPs contain a conserved catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. One such specific subdomain, the DUSP domain ( domain present in ubiquitin-specific proteases), is present in at least seven different human USPs that regulate the stability of or interact with the hypoxia-inducible transcription factor HIF1-alpha, the Von Hippel-Lindau protein ( pVHL), cullin E3 ligases, and BRCA2. We describe the NMR solution structure of the DUSP domain of human USP15, recently implicated in COP9 ( constitutive photomorphogenic gene 9) -signalosome regulation. Its tripod-like structure consists of a 3-fold alpha-helical bundle supporting a triple-stranded anti-parallel alpha-sheet. The DUSP domain displays a novel fold, an alpha/beta tripod ( AB3). DUSP domain surface properties and previously described work suggest a potential role in protein/protein interaction or substrate recognition.