Abstract
Endogenous lipids play essential roles in modulating membrane protein structure and function, yet the molecular mechanisms governing lipid-specific regulation remain elusive. Here, we combine solid-state NMR spectroscopy and molecular dynamics simulations to elucidate how distinct lipids regulate the structure and activity of a membrane protein in a native-like membrane environment. Using VsSemiSWEET as a model system, we determine its high-resolution structure with bound lipids, identifying three lipid types: phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CDL). These lipids bind at the monomer-monomer interface, stabilizing the dimeric structure of VsSemiSWEET. Notably, PG and CDL exhibit differential binding modes, with CDL demonstrating a dual interaction mechanism involving both its headgroup and acyl chains that enhances both dimer stability and functional activity. These findings reveal how lipids with different physicochemical properties differentially control membrane protein oligomerization and function, providing a mechanistic framework for lipid-specific regulation.
Data availability
Solid-state NMR chemical shifts have been deposited in the Biological Magnetic Resonance Bank (BMRB) with ID number 51331. The atomic coordinates for the solid-state NMR structure have been deposited in the Protein Data Bank (PDB) under accession code 9KON (Structure of VsSemiSWEET in lipid bilayers determined by solid-state NMR). Published structure discussed or analyzed in this work: 4QND. All relevant data that support the findings of this study are provided in the article and supplementary Information. Source data are provided as a Source Data file.
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Acknowledgements
This work was funded by grants from the National Natural Science Foundation of China (22434003, 22507127, 22577099, 21927801, 21991081, 21921004, and 22004124), the Chinese Academy of Sciences (YJKYYQ20190032 and XDB0540000), the Hubei Provincial Natural Science Foundation of China (2024AFA005 and 2025AFB512), Start-up Research Funding for Newly Recruited Faculty at Nanjing Medical University (KY101RC20250008), and the China Postdoctoral Science Foundation (2020M672455, 2024M752494, and GZC20241290).
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Y.Z. and J.Y. conceived the study. Y.Z., M.D., and J.Y. designed the experiments. J.L., W.Z., and Q.T. performed biochemistry experiments. W.Z. Y.-X.Z. and Y.Z. prepared the NMR samples. Y.Z. performed NMR experiments. Y.Z. and H.X. performed structural biology experiments. M.D. constructed the MD simulations. Y.S. built and refined structural models. All authors analyzed the results. Y.Z., W.Z., M.D. and J.Y. interpreted the data and wrote the manuscript.
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Zhang, Y., Zhao, W., Duan, M. et al. Diverse regulation of functional dimerization of a sugar transporter by different interfacial lipids. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69804-3
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DOI: https://doi.org/10.1038/s41467-026-69804-3
