Diverse regulation of functional dimerization of a sugar transporter by different interfacial lipids

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 Vs SemiSWEET 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 Vs SemiSWEET. 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.