title: Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A.
abstract: Cdc25 phosphatases activate the cell division kinases throughout the cell cycle. The 2.3 A structure of the human Cdc25A catalytic domain reveals a small alpha/beta domain with a fold unlike previously described phosphatase structures but identical to rhodanese, a sulfur-transfer protein. Only the active-site loop, containing the Cys-(X)5-Arg motif, shows similarity to the tyrosine phosphatases. In some crystals, the catalytic Cys-430 forms a disulfide bond with the invariant Cys-384, suggesting that Cdc25 may be self-inhibited during oxidative stress. Asp-383, previously proposed to be the general acid, instead serves a structural role, forming a conserved buried salt-bridge. We propose that Glu-431 may act as a general acid. Structure-based alignments suggest that the noncatalytic domain of the MAP kinase phosphatases will share this topology, as will ACR2, a eukaryotic arsenical resistance protein.
authors.affiliation: Department of Biological Chemistry, The University of Michigan, Ann Arbor 48109-1055, USA. fauman@umich.edu
authors.forename: E B
authors.initials: EB
authors.lastname: Fauman
authors.forename: J P
authors.initials: JP
authors.lastname: Cogswell
authors.forename: B
authors.initials: B
authors.lastname: Lovejoy
authors.forename: W J
authors.initials: WJ
authors.lastname: Rocque
authors.forename: W
authors.initials: W
authors.lastname: Holmes
authors.forename: V G
authors.initials: VG
authors.lastname: Montana
authors.forename: H
authors.initials: H
authors.lastname: Piwnica-Worms
authors.forename: M J
authors.initials: MJ
authors.lastname: Rink
authors.forename: M A
authors.initials: MA
authors.lastname: Saper
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D016415:Sequence Alignment; D013379:Substrate Specificity; D020687:cdc25 Phosphatases
chemical_list: D004220:Disulfides; C517004:CDC25A protein, human; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases