Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.

ABSTRACT: WNT/β-catenin signaling plays key roles in development and cancer^1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling^3-5. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane h

SUBMITTER: Wang L 

PROVIDER: S-EPMC11698847 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature