Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6
Jennifer L Stamos,
Matthew Ling-Hon Chu,
Michael D Enos,
Niket Shah,
William I Weis
Affiliations
Jennifer L Stamos
Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
Matthew Ling-Hon Chu
Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
Michael D Enos
Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
Niket Shah
Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
William I Weis
Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
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.
