Native mass spectrometry of membrane protein lipid and ligand complexes using de novo designed WRAP domains
Kokane, S.; Mihaljevic, L.; Abreu, B.; de Schepper, S.; Stevens, A.; Marklund, E.; Baker, D.; Stansfeld, P. J.; Landreh, M.
Show abstract
Membrane proteins engage in dynamic transient interactions with surrounding lipids along with their substrates. Capturing these concomitant contacts often remains a challenging problem. Here, we demonstrate that generative deep learning-designed WRAP domains can preserve weak interactions of membrane protein complexes in native mass spectrometry. Using WRAP-fused GlpG, AqpM, and OmpA as model systems, we show that lipid interactions can be retained and characterized without detergent micelles. We use the approach to show that WRAP-OmpA selectively binds phosphatidylethanolamine lipids within cavities formed at the protein-WRAP interface, while simultaneously accommodating weak chitobiose ligand binding. These findings establish WRAPs as versatile vehicles to probe ligand and lipid interactions of membrane proteins.
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