8g4y

From Proteopedia

Structure of ZNRF3 ECD bound to peptide MK1-3.6.10

Structural highlights

8g4y is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.41Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ZNRF3_HUMAN Adrenocortical carcinoma.

Function

ZNRF3_HUMAN E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby restricting the size of the intestinal stem cell zone (PubMed:22575959). Along with RSPO2 and RNF43, constitutes a master switch that governs limb specification (By similarity).[UniProtKB:Q08D68]^[1]

Publication Abstract from PubMed

Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.

Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.,Kschonsak YT, Gao X, Miller SE, Hwang S, Marei H, Wu P, Li Y, Ruiz K, Dorighi K, Holokai L, Perampalam P, Tsai WK, Kee YS, Agard NJ, Harris SF, Hannoush RN, de Sousa E Melo F Cell Chem Biol. 2024 Jun 20;31(6):1176-1187.e10. doi: , 10.1016/j.chembiol.2023.11.006. Epub 2023 Dec 5. PMID:38056465^[2]

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

References

↑ 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
↑ Kschonsak YT, Gao X, Miller SE, Hwang S, Marei H, Wu P, Li Y, Ruiz K, Dorighi K, Holokai L, Perampalam P, Tsai WK, Kee YS, Agard NJ, Harris SF, Hannoush RN, de Sousa E Melo F. Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth. Cell Chem Biol. 2023 Nov 30:S2451-9456(23)00421-X. PMID:38056465 doi:10.1016/j.chembiol.2023.11.006