title: Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6.
abstract: Glycogen synthase kinase-3 (GSK-3) is a key regulator of many cellular signaling pathways. Unlike most kinases, GSK-3 is controlled by inhibition rather than by specific activation. In the insulin and several other signaling pathways, phosphorylation of a serine present in a conserved sequence near the amino terminus of GSK-3 generates an auto-inhibitory peptide. In contrast, Wnt/β-catenin signal transduction requires phosphorylation of Ser/Pro rich sequences present in the Wnt co-receptors LRP5/6, and these motifs inhibit GSK-3 activity. We present crystal structures of GSK-3 bound to its phosphorylated N-terminus and to two of the phosphorylated LRP6 motifs. A conserved loop unique to GSK-3 undergoes a dramatic conformational change that clamps the bound pseudo-substrate peptides, and reveals the mechanism of primed substrate recognition. The structures rationalize target sequence preferences and suggest avenues for the design of inhibitors selective for a subset of pathways regulated by GSK-3. DOI: http://dx.doi.org/10.7554/eLife.01998.001.
authors.affiliation: Department of Structural Biology, Stanford University, Stanford, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stamos
authors.forename: Matthew Ling-Hon
authors.initials: ML
authors.lastname: Chu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Enos
authors.forename: Niket
authors.initials: N
authors.lastname: Shah
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D038362:Glycogen Synthase Kinase 3
keywords: GSK-3; LRP6; Wnt signaling; protein kinase