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. 2025 Jan 3;16:362. doi: 10.1038/s41467-024-55431-3

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© The Author(s) 2025

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

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Fig. 4 — The transmembrane interface between LGR4 and ZNRF3 in the LGR4-RSPO2-ZNRF3(ΔRING) complex (2:2:2, di-heterotrimer) is shown from the front view (a), top view (b) and bottom view (c). d The interface between the transmembrane domains of LGR4 and ZNRF3. e, f The side chain interactions between LGR4 and ZNRF3 within the transmembrane region of the LGR4-RSPO2(Fu)-ZNRF3(ΔRING) complex (2:2:2) are shown in detail. g The specific interactions between the transmembrane domain of LGR4, ZNRF3 and cholesteryl hemisuccinate within the LGR4-RSPO2(Fu)-ZNRF3(ΔRING) complex (2:2:2) are highlighted. h, i Dose-dependent TOPFlash activity induced by WT (black) or W751A^6.39 mutant (red, e) and F804A^7.56 mutant (green, f) of LGR4 after stimulation with RSPO1, n = 3. Source data are provided as a Source Data file. j–l Comparing the LGR4 in pentamer B and di-heterotrimer. j The model of LGR4-RSPO2ZNRF3(RING) (1:2:2, pentamer B). k The surface of two LGR4 in LGR4-RSPO2ZNRF3(ΔRING) (2:2:2, di-heterotrimer). l Superposition of the LGR4 in pentamer B and di-heterotrimer (ZNRF3 and RSPO2 are deleted for clarity). m, n Conformational comparison of the TMD of LGR4 (light blue) in the di-heterotrimer with that of active LHCGR (wheat, PDB:7FII, RMSD = 1.524, 182 to 182 atoms) from the front view (m), and bottom view (n). The potential steric clash between TM6 of the active LGR4 and the single TM helix (violet) of ZNRF3 in the di-heterotrimer complex is shown. o TOPFlash plot illustrating the effect of breaking ionic lock (Q742K^6.30 mutant) (purple) in the transmembrane domain of LGR4 on the activity of RSPO1, compared to that of WT (black), n = 4. Source data are provided as a Source Data file. Each value represents the mean ± SEM from independent experiments. The LGR4(WT) datasets in all three panels are identical.