4kt1

From Proteopedia
Jump to navigation Jump to search

Complex of R-spondin 1 with LGR4 extracellular domainComplex of R-spondin 1 with LGR4 extracellular domain

Structural highlights

4kt1 is a 2 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 2.497Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RSPO1_HUMAN Palmoplantar keratoderma - XX sex reversal - predisposition to squamous cell carcinoma. Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC) [MIM:610644: A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Note=The disease is caused by mutations affecting the gene represented in this entry.

Function

RSPO1_HUMAN Activator of the beta-catenin signaling cascade, leading to TCF-dependent gene activation. Acts both in the canonical Wnt/beta-catenin-dependent pathway and in non-canonical Wnt signaling pathway, probably by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination.[1] [2]

Publication Abstract from PubMed

The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.

Structural basis for R-spondin recognition by LGR4/5/6 receptors.,Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X Genes Dev. 2013 Jun 15;27(12):1339-44. doi: 10.1101/gad.219360.113. Epub 2013 Jun, 11. PMID:23756652[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, Funk WD, Tomizuka K. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 2005 Aug 19;309(5738):1256-9. PMID:16109882 doi:309/5738/1256
  2. ↑ Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, Lei H, Mickanin C, Liu D, Ruffner H, Mao X, Ma Q, Zamponi R, Bouwmeester T, Finan PM, Kirschner MW, Porter JA, Serluca FC, Cong F. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012 Apr 29;485(7397):195-200. doi: 10.1038/nature11019. PMID:22575959 doi:10.1038/nature11019
  3. ↑ Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X. Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev. 2013 Jun 15;27(12):1339-44. doi: 10.1101/gad.219360.113. Epub 2013 Jun, 11. PMID:23756652 doi:10.1101/gad.219360.113

4kt1, resolution 2.50Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=4kt1&oldid=4216172"