Abstract
<jats:p>Lipids play diverse physiological roles in energy storage, signaling, and cell structure. Another less appreciated role is as allosteric modulators of membrane proteins. However, it is challenging to determine the identify and affinity of lipids interacting with a given membrane protein target. In this review, we discuss analytical advances in using lipidomics to profile lipids bound to specific membrane proteins, which we will refer to as protein-lipid interactomics. We will consider the challenges of solubilizing and isolating the membrane protein while retaining relevant lipid interactions, focusing on detergents and lipid nanoparticles made with polymer, peptide, and protein scaffolds. We will also discuss aspects of overall experiment design, including basic identification, quantitative experiments, progressive delipidation, and lipid exchange to probe the strength of lipid interactions. Finally, we conclude with key questions, current analytical challenges, and proposed future directions for this emerging field.</jats:p>