Due to their important biochemical roles, membrane proteins are important drug targets. Although it is clear that lipids can influence membrane protein function, the chemistry of lipid binding remains difficult to study because protein-lipid interactions are polydisperse, competitive, and transient. We have been developing new approaches to quantify protein-lipid interactions in bilayers and understand how membrane proteins remodel their surrounding lipid environment. In one new approach, we use mass spectrometry (MS) to quantify the exchange of lipids between lipoprotein nanodiscs with and without an embedded membrane protein. Shifts in the lipid distribution towards the membrane protein nanodiscs reveal lipid binding, and titrations allow measurement of the optimal lipid composition for the membrane protein. Second, we use native MS to ionize membrane protein nanodiscs with heterogeneous lipids. Ejecting the membrane protein complex with bound lipids in the mass spectrometer revealed enrichment of specific lipids around the membrane protein. Ultimately, we expect these unique combinations of nanodiscs and MS will provide new insights into the chemistry and selectivity of membrane protein-lipid interactions.

Combining mass spectrometry and nanodiscs to investigate membrane protein-lipid interactions

ACS Spring 2022

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