Research Projects

G protein-coupled receptors (GPCRs) are vital membrane proteins that regulate nearly all physiological processes and are the target of approximately 40% of current drugs. These transmembrane sensors engage with three main signaling effectors: G proteins, which initiate primary signal transduction; G protein-coupled receptor kinases (GRKs), which phosphorylate the receptor; and arrestins, which bind phosphorylated receptors to enable G protein-independent pathways. Recent structural studies on over 350 GPCRs have greatly enhanced our understanding of ligand binding, receptor activation, and conformational changes. Yet, these studies often employ detergent micelles, extracting GPCRs from their native lipid environment and disrupting crucial lipid interactions that are key to understanding their full physiological roles. Advancements in GPCR structural biology, such as the structural determination of the dopamine D2 receptor, neurotensin receptor type 1, and rhodopsin in lipid bilayer systems like nanodiscs, have underscored that lipids play an essential role in receptor function. For instance, the interaction of cholesterol with GPCRs has been shown to affect receptor activation, dimerization, and stability. While cholesterol’s influence is well documented, the role of other lipids, especially phospholipids, in shaping GPCR structure and signaling remains underexplored. Given the GPCRs’ intricate association with cell membranes, it is evident that surrounding lipids profoundly influence their behavior. The biochemical diversity of phospholipids introduces complexity, with their unique head groups and hydrocarbon chains impacting receptor-lipid interactions. Emerging evidence indicates that specific phospholipids may bind to GPCRs, with electrostatic interactions between these lipids and positively charged residues on the receptor’s cytoplasmic face playing a significant signaling role. Membrane lipid composition varies in disease states, influencing conditions such as cancer and neurodegenerative diseases and suggesting their potential as biomarkers or therapeutic targets. My research focuses on how phospholipids regulate the function of Lysophosphatidic Acid Receptor 2 (LPAR2), a GPCR activated by the lipid lysophosphatidic acid (LPA). LPA-induced LPAR2 activation promotes cancer cell migration and metastasis, particularly in breast and ovarian cancers, making LPAR2 a compelling therapeutic target. By reconstituting LPAR2 in nanodiscs that mimic its natural lipid environment, I aim to explore how phospholipids impact its signaling, especially in β-arrestin-mediated pathways relevant to cancer progression, which is currently not understood. Using advanced biophysical and biochemical techniques, this work seeks to clarify the role of lipid modulation in GPCR function, paving the way for lipid-targeted therapies and novel approaches to treating diseases driven by lipid dysregulation.