Structural insights into the engagement of lysophosphatidic acid receptor 1 with different G proteins

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive lysophospholipids derived from cell membranes that activate the endothelial differentiation gene family of G protein-coupled receptors. Activation of these receptors triggers multiple downstream signaling cascades through G proteins such as Gi/o, Gq/ 11, and G12/13. Therefore, LPA and S1P mediate several physiological processes, including cytoskeletal dynamics, neurite retraction, cell migration, cell proliferation, and intracellular ion fluxes. The basis for the Gprotein coupling selectivity of EDG receptors, however, remains unknown. Here, we present cryo-electron microscopy structures of LPA-activated LPA1 in complexes with Gi, Gq, and G 13 heterotrimers. Comparison of the three LPA1-G protein structures shows clearly different conformations of intracellular loop 2 (ICL2) and ICL3 that are likely induced by the different G alpha protein interfaces. Interestingly, this G-protein interface interaction is a common feature of LPA and S1P receptors. Our findings provide clues to understanding the promiscuity of Gprotein coupling in the endothelial differentiation gene family.