Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2014-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/01998 |
| _version_ | 1811200302168145920 |
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| author | Jennifer L Stamos Matthew Ling-Hon Chu Michael D Enos Niket Shah William I Weis |
| author_facet | Jennifer L Stamos Matthew Ling-Hon Chu Michael D Enos Niket Shah William I Weis |
| author_sort | Jennifer L Stamos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:02:29Z |
| format | Article |
| id | doaj.art-7c15a261e8bd48adb929dd7023bf8741 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:02:29Z |
| publishDate | 2014-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7c15a261e8bd48adb929dd7023bf87412022-12-22T03:52:38ZengeLife Sciences Publications LtdeLife2050-084X2014-03-01310.7554/eLife.01998Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6Jennifer L Stamos0Matthew Ling-Hon Chu1Michael D Enos2Niket Shah3William I Weis4Department of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United StatesDepartment of Structural Biology, Stanford University, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University, Stanford, United StatesGlycogen 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.https://elifesciences.org/articles/01998GSK-3Wnt signalingprotein kinaseLRP6 |
| spellingShingle | Jennifer L Stamos Matthew Ling-Hon Chu Michael D Enos Niket Shah William I Weis Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 eLife GSK-3 Wnt signaling protein kinase LRP6 |
| title | Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 |
| title_full | Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 |
| title_fullStr | Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 |
| title_full_unstemmed | Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 |
| title_short | Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6 |
| title_sort | structural basis of gsk 3 inhibition by n terminal phosphorylation and by the wnt receptor lrp6 |
| topic | GSK-3 Wnt signaling protein kinase LRP6 |
| url | https://elifesciences.org/articles/01998 |
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