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LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands

Scientific reports, 2023-07, Vol.13 (1), p.10796-10796, Article 10796 [Peer Reviewed Journal]

2023. The Author(s). ;The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s) 2023 ;ISSN: 2045-2322 ;EISSN: 2045-2322 ;DOI: 10.1038/s41598-023-37856-w ;PMID: 37402772

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  • Title:
    LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands
  • Author: Toh, Yukimatsu ; Wu, Ling ; Park, Soohyun ; Wang, Allison ; Tu, Jianghua ; Yu, Wangsheng ; Zuo, Mingxin ; Carmon, Kendra S ; Liu, Qingyun J
  • Subjects: Affinity ; Furin ; Ligands ; Receptors, G-Protein-Coupled - metabolism ; Thrombospondins - metabolism ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - metabolism ; Wnt protein ; Wnt Signaling Pathway ; β-Catenin
  • Is Part Of: Scientific reports, 2023-07, Vol.13 (1), p.10796-10796, Article 10796
  • Description: LGR4 and LGR5 are two homologous receptors that potentiate Wnt/β-catenin signaling in response to R-spondin (RSPO) ligands. The RSPO and LGR4 complex binds to and inhibits activities of two related E3 ubiquitin ligases, RNF43 and ZNRF3, and thus protects Wnt receptors from the E3 ligase-mediated degradation. The RSPO and LGR5 complex, however, does not interact with the E3 ligases, and the structural basis of this difference remained unknown. Here we examined the affinities of monovalent and bivalent RSPO ligands in binding to LGR4, RNF43/ZNRF3, and LGR5 in whole cells and found unique features among the receptors and E3 ligases. Monovalent RSPO2 furin domain had much lower affinity in binding to LGR4 or RNF43/ZNRF3 than the bivalent form. In contrast, monovalent and bivalent forms had nearly identical affinity in binding to LGR5. Co-expression of ZNRF3 with LGR4 led to much higher binding affinity of the monovalent form whereas co-expression of ZNRF3 with LGR5 had no effect on the affinity. These results suggest that LGR4 and RNF43/ZNRF3 form a 2:2 dimer that accommodates bivalent binding of RSPO whereas LGR5 forms a homodimer that does not. Structural models are proposed to illustrate how RSPOs bind to LGR4, RNF43/ZNRF3, and LGR5 in whole cells.
  • Publisher: England: Nature Publishing Group
  • Language: English
  • Identifier: ISSN: 2045-2322
    EISSN: 2045-2322
    DOI: 10.1038/s41598-023-37856-w
    PMID: 37402772
  • Source: MEDLINE
    PubMed Central
    ProQuest Central
    DOAJ Directory of Open Access Journals
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