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5un5

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Revision as of 14:35, 6 November 2017

Frizzled-8 complex with designed surrogate Wnt agonist, crystal form 1

Structural highlights

5un5 is a 4 chain structure with sequence from Human and Synthetic construct sequences. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	5un6
Gene:	FZD8 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FZD8_HUMAN] Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Coreceptor along with RYK of Wnt proteins, such as WNT1.^[1]

Publication Abstract from PubMed

Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing beta-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic beta-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling.,Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, Yan KS, Marecic O, Siepe D, Li X, Moody JD, Williams BO, Clevers H, Piehler J, Baker D, Kuo CJ, Garcia KC Nature. 2017 May 11;545(7653):234-237. doi: 10.1038/nature22306. Epub 2017 May 3. PMID:28467818^[2]

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
↑ Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, Yan KS, Marecic O, Siepe D, Li X, Moody JD, Williams BO, Clevers H, Piehler J, Baker D, Kuo CJ, Garcia KC. Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling. Nature. 2017 May 11;545(7653):234-237. doi: 10.1038/nature22306. Epub 2017 May 3. PMID:28467818 doi:http://dx.doi.org/10.1038/nature22306

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5un5"

@@ Line 3: / Line 3: @@
 <StructureSection load='5un5' size='340' side='right' caption='[[5un5]], [[Resolution|resolution]] 2.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5un5]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UN5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UN5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5un5]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UN5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UN5 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5un6|5un6]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FZD8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5un5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5un5 OCA], [http://pdbe.org/5un5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5un5 RCSB], [http://www.ebi.ac.uk/pdbsum/5un5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5un5 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Synthetic construct sequences]]
 [[Category: Garcia, K C]]
 [[Category: Janda, C Y]]
 [[Category: Signaling protein]]
 [[Category: Signaling protein-de novo protein complex]]

5un5

From Proteopedia

Revision as of 14:35, 6 November 2017

Frizzled-8 complex with designed surrogate Wnt agonist, crystal form 1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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