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

Lu Wang1, Fangzheng Hu1, Qianqian Cui1

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Nature Communications
|January 3, 2025
PubMed

Insights

The LGR4 protein content dictates the assembly and conformation of ZNRF3, regulating WNT/β-catenin signaling. This structural understanding is crucial for developing drugs targeting Wnt-driven cancers.

Area of Science:

  • Biochemistry and structural biology
  • Cell signaling pathways
  • Cancer research

Background:

  • WNT/β-catenin signaling is vital for development and cancer.
  • ZNRF3/RNF43 proteins regulate this pathway by ubiquitination.
  • RSPO proteins enhance WNT signaling by binding LGR4-6 and ZNRF3/RNF43.

Purpose of the Study:

  • To elucidate the structural architectures of LGR4, RSPO2, and ZNRF3 assemblies.
  • To understand how varying stoichiometries and arrangements influence ZNRF3 conformation and WNT signaling.
  • To provide a structural basis for targeting Wnt-driven cancers.

Main Methods:

  • Analysis of multiple LGR4, RSPO2, and ZNRF3 assembly structures.
  • Characterization of varying stoichiometries and arrangements within these complexes.
  • Investigation of LGR4 content's influence on ZNRF3 conformation.

Main Results:

  • LGR4 and RSPO2 capture distinct ZNRF3 states.
  • A 2:2:2 LGR4-RSPO2-ZNRF3 complex stabilizes inactive ZNRF3 via inward-open transmembrane helices, promoting endocytosis.
  • A complex with one LGR4 stabilizes active, dimeric ZNRF3 with a coiled-coil transmembrane helix conformation.

Conclusions:

  • LGR4 content mediates diverse assemblies, inducing conformational changes in ZNRF3.
  • These structural insights reveal mechanisms for regulating WNT/β-catenin signaling.
  • Findings offer a structural foundation for developing drugs against Wnt-driven cancers.

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