title: Ubiquitin-specific protease 4 is inhibited by its ubiquitin-like domain.
abstract: USP4 is a member of the ubiquitin-specific protease (USP) family of deubiquitinating enzymes that has a role in spliceosome regulation. Here, we show that the crystal structure of the minimal catalytic domain of USP4 has the conserved USP-like fold with its typical ubiquitin-binding site. A ubiquitin-like (Ubl) domain inserted into the catalytic domain has autoregulatory function. This Ubl domain can bind to the catalytic domain and compete with the ubiquitin substrate, partially inhibiting USP4 activity against different substrates. Interestingly, other USPs, such as USP39, could relieve this inhibition.
authors.affiliation: Division of Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Mark P A
authors.initials: MP
authors.lastname: Luna-Vargas
authors.forename: Alex C
authors.initials: AC
authors.lastname: Faesen
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van Dijk
authors.forename: Michael
authors.initials: M
authors.lastname: Rape
authors.forename: Alexander
authors.initials: A
authors.lastname: Fish
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase / Q000737:chemistry* / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases
chemical_list: C486203:USP4 protein, human; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases