| Structural highlights
8ffe is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.72Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
LRP6_HUMAN Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis. The disease is caused by mutations affecting the gene represented in this entry.
Function
LRP6_HUMAN Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate beta-catenin signaling. The cryo-EM structure of a ternary initiation complex of an affinity-matured XWnt8-Frizzled8-LRP6 complex elucidates the basis of coreceptor discrimination by canonical Wnts by means of their N termini and linker domains that engage the LRP6 E1E2 domain funnels. Chimeric Wnts bearing modular linker "grafts" were able to transfer LRP6 domain specificity between different Wnts and enable non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain serve as Wnt-specific antagonists. The structure of the ternary complex provides a topological blueprint for the orientation and proximity of Frizzled and LRP6 within the Wnt cell surface signalosome.
Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.,Tsutsumi N, Hwang S, Waghray D, Hansen S, Jude KM, Wang N, Miao Y, Glassman CR, Caveney NA, Janda CY, Hannoush RN, Garcia KC Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2218238120. doi: , 10.1073/pnas.2218238120. Epub 2023 Mar 9. PMID:36893265[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001 Jun 26;11(12):951-61. PMID:11448771
- ↑ Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 2001 May 17;411(6835):321-5. PMID:11357136 doi:10.1038/35077108
- ↑ Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005 May 20;280(20):19883-7. Epub 2005 Mar 18. PMID:15778503 doi:10.1074/jbc.M413274200
- ↑ Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005 Dec 8;438(7069):873-7. PMID:16341017 doi:10.1038/nature04185
- ↑ Swiatek W, Kang H, Garcia BA, Shabanowitz J, Coombs GS, Hunt DF, Virshup DM. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem. 2006 May 5;281(18):12233-41. Epub 2006 Mar 2. PMID:16513652 doi:10.1074/jbc.M510580200
- ↑ Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J Biol Chem. 2007 May 25;282(21):15903-11. Epub 2007 Mar 30. PMID:17400545 doi:10.1074/jbc.M701927200
- ↑ Mi K, Johnson GV. Regulated proteolytic processing of LRP6 results in release of its intracellular domain. J Neurochem. 2007 Apr;101(2):517-29. Epub 2007 Feb 26. PMID:17326769 doi:10.1111/j.1471-4159.2007.04447.x
- ↑ Piao S, Lee SH, Kim H, Yum S, Stamos JL, Xu Y, Lee SJ, Lee J, Oh S, Han JK, Park BJ, Weis WI, Ha NC. Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS One. 2008;3(12):e4046. doi: 10.1371/journal.pone.0004046. Epub 2008 Dec 24. PMID:19107203 doi:10.1371/journal.pone.0004046
- ↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
- ↑ Wu G, Huang H, Garcia Abreu J, He X. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One. 2009;4(3):e4926. doi: 10.1371/journal.pone.0004926. Epub 2009 Mar 18. PMID:19293931 doi:10.1371/journal.pone.0004926
- ↑ Tsutsumi N, Hwang S, Waghray D, Hansen S, Jude KM, Wang N, Miao Y, Glassman CR, Caveney NA, Janda CY, Hannoush RN, Garcia KC. Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2218238120. PMID:36893265 doi:10.1073/pnas.2218238120
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