6h15

From Proteopedia

(Difference between revisions)

Current revision

Structure of LRP6 P3E3P4E4 in complex with VHH L-P2-B10

Structural highlights

6h15 is a 4 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
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-induced beta-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced beta-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected. Structural analysis reveal that individual VHHs variably employ divergent antigen-binding regions to bind a similar surface in the third beta-propeller of LRP5/6, sterically interfering with Wnt3/3a binding. Importantly, anti-LRP5/6 VHHs block the growth of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids through stem cell exhaustion and collective terminal differentiation. Thus, VHH-mediated targeting of LRP5/6 provides a promising differentiation-inducing strategy for treatment of Wnt-hypersensitive tumors.

Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells.,Fenderico N, van Scherpenzeel RC, Goldflam M, Proverbio D, Jordens I, Kralj T, Stryeck S, Bass TZ, Hermans G, Ullman C, Aastrup T, Gros P, Maurice MM Nat Commun. 2019 Jan 21;10(1):365. doi: 10.1038/s41467-018-08172-z. PMID:30664649^[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
↑ Fenderico N, van Scherpenzeel RC, Goldflam M, Proverbio D, Jordens I, Kralj T, Stryeck S, Bass TZ, Hermans G, Ullman C, Aastrup T, Gros P, Maurice MM. Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells. Nat Commun. 2019 Jan 21;10(1):365. doi: 10.1038/s41467-018-08172-z. PMID:30664649 doi:http://dx.doi.org/10.1038/s41467-018-08172-z

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6h15"

Categories: Homo sapiens | Lama glama | Large Structures | Gros P | Van Scherpenzeel RC

@@ Line 1: / Line 1: @@
 ==Structure of LRP6 P3E3P4E4 in complex with VHH L-P2-B10==
-<StructureSection load='6h15' size='340' side='right' caption='[[6h15]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='6h15' size='340' side='right'caption='[[6h15]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6h15]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H15 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H15 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6h15]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6H15 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6h15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h15 OCA], [http://pdbe.org/6h15 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h15 RCSB], [http://www.ebi.ac.uk/pdbsum/6h15 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h15 ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6h15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h15 OCA], [https://pdbe.org/6h15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6h15 RCSB], [https://www.ebi.ac.uk/pdbsum/6h15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6h15 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/LRP6_HUMAN LRP6_HUMAN]] Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis. The disease is caused by mutations affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/LRP6_HUMAN LRP6_HUMAN] Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis. The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[http://www.uniprot.org/uniprot/LRP6_HUMAN 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).<ref>PMID:11448771</ref> <ref>PMID:11357136</ref> <ref>PMID:15778503</ref> <ref>PMID:16341017</ref> <ref>PMID:16513652</ref> <ref>PMID:17400545</ref> <ref>PMID:17326769</ref> <ref>PMID:19107203</ref> <ref>PMID:19801552</ref> <ref>PMID:19293931</ref>
+[https://www.uniprot.org/uniprot/LRP6_HUMAN 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).<ref>PMID:11448771</ref> <ref>PMID:11357136</ref> <ref>PMID:15778503</ref> <ref>PMID:16341017</ref> <ref>PMID:16513652</ref> <ref>PMID:17400545</ref> <ref>PMID:17326769</ref> <ref>PMID:19107203</ref> <ref>PMID:19801552</ref> <ref>PMID:19293931</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 6h15" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Antibody 3D structures|Antibody 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Gros, P]]
+[[Category: Homo sapiens]]
-[[Category: Scherpenzeel, R C.van]]
+[[Category: Lama glama]]
-[[Category: Complex]]
+[[Category: Large Structures]]
-[[Category: Inhibitor]]
+[[Category: Gros P]]
-[[Category: Signaling protein]]
+[[Category: Van Scherpenzeel RC]]

6h15

From Proteopedia

Current revision

Structure of LRP6 P3E3P4E4 in complex with VHH L-P2-B10

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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