Native ion mobility mass spectrometry (MS) is an emerging biophysical technique to probe soluble and membrane protein complexes and their interactions with small molecules, such as drugs and lipids. I will highlight our recent work on the two-pore domain potassium channel, TRAAK.  We find the channel displays distinct binding preferences for lipids that is dependent on acyl chain length and position on the glycerol backbone. Surprisingly, the channel can also discriminate the fatty acid linkage at the <i>sn-1</i> position. Phosphatidic acid had the lowest equilibrium dissociation constants for TRAAK and activates the channel in dose-dependent fashion. I then will discuss our work probing lipid binding to different a G-protein-gated inward rectifying potassium channel, Kir3.2. These studies are complemented with variable temperature electrospray ionization to determine binding thermodynamics.  We find Kir3.2 displays distinct thermodynamic strategies to engage phospholipids.  In some cases, binding is driven by favorable entropy and enthalpy whereas for other lipids binding is driven solely by entropy.

Native mass spectrometry of membrane proteins in complex with lipids

ACS Spring 2022

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