title: A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.
abstract: The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "nonprimed" substrates in the Wnt-signaling pathway (Axin and beta-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.
authors: Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, DD1 5EH, Dundee, United Kingdom.
authors: S
authors: S
authors: Frame
authors: P
authors: P
authors: Cohen
authors: R M
authors: RM
authors: Biondi
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism; D060466:Axin Protein; D001665:Binding Sites / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D007930:Leucine / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010710:Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D010710:Phosphates; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; D012694:Serine; D001120:Arginine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007930:Leucine