title: Phosphorylation-dependent activity of the deubiquitinase DUBA.
abstract: Addition and removal of ubiquitin or ubiquitin chains to and from proteins is a tightly regulated process that contributes to cellular signaling and protein stability. Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. The crystal structure of the ubiquitin aldehyde adduct of active DUBA reveals a marked cooperation between phosphorylation and substrate binding. An intricate web of interactions involving the phosphate and the C-terminal tail of ubiquitin cause DUBA to fold around its substrate, revealing why phosphorylation is essential for deubiquitinase activity. Phosphoactivation of DUBA represents an unprecedented mode of protease regulation and a clear link between two major cellular signal transduction systems: phosphorylation and ubiquitin modification.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, South San Francisco, California, USA.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.forename: JianPing
authors.initials: J
authors.lastname: Yin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Flinders
authors.forename: Till
authors.initials: T
authors.lastname: Maurer
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Qui
authors.initials: Q
authors.lastname: Phung
authors.forename: Ivan
authors.initials: I
authors.lastname: Bosanac
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D012694:Serine / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D012694:Serine; D010450:Endopeptidases; C525076:OTUD5 protein, human