| Structural highlights
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
LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem beta-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites.
Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt Signaling.,Chen S, Bubeck D, Macdonald BT, Liang WX, Mao JH, Malinauskas T, Llorca O, Aricescu AR, Siebold C, He X, Jones EY Dev Cell. 2011 Oct 11. PMID:22000855[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
- ↑ Chen S, Bubeck D, Macdonald BT, Liang WX, Mao JH, Malinauskas T, Llorca O, Aricescu AR, Siebold C, He X, Jones EY. Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt Signaling. Dev Cell. 2011 Oct 11. PMID:22000855 doi:10.1016/j.devcel.2011.09.007
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