title: Pin1 acts catalytically to promote a conformational change in Cdc25.
abstract: Pin1 is an essential protein that can peptidyl-prolyl-isomerize small phosphopeptides. It has been suggested that Pin1 regulates entry into mitosis by catalyzing the cis/trans-isomerization of prolines on critical protein substrates in response to phosphorylation. We show that Pin1 catalytically generates a conformational change on the mitotic phosphatase Cdc25, as assayed by limited protease digestion, differential reactivity to a phosphoserine-proline-directed monoclonal antibody (MPM-2), and by changes in Cdc25 enzymatic activity. Pin1 catalytically modifies the conformation of Cdc25 at stoichiometries less than 0.0005, and mutants of Pin1 in the prolyl isomerase domain are not active. We suggest that, although difficult to detect, phosphorylation-dependent conformational changes mediated by prolyl isomerization may play an important regulatory role in the cell cycle.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Medical School, Charlottesville, VA 22908, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Stukenberg
authors.forename: M W
authors.initials: MW
authors.lastname: Kirschner
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000494:pharmacology*; D010766:Phosphorylation; D011392:Proline / Q000187:drug effects; D011487:Protein Conformation; D014981:Xenopus; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011392:Proline; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase