GPCR biology in autoimmunity: bridging genetics to structure to decipher mechanisms of disease

PROJECT SUMMARY/ABSTRACT Genome-wide association studies have implicated multiple genetic variants of G-protein coupled receptors (GPCRs) in immune-mediated diseases. Translating genetic associations into tangible effects on protein function remains a significant challenge. Here, we will leverage advancements in biophysics and structural biology to discern how coding variants in prioritized GPCRs alter structure, function, and downstream signaling. Insights from these studies will be used to devise therapeutic hypotheses and to test experimental interventions that target genetic mechanisms of disease. Specifically, we will (1) Define the structural basis for impaired function of the autoimmunity-associated GPR65 variant and rescue by positive allosteric modulators, (2) Define the structural basis for autoimmunity-associated PTAFR variant and its gain-of-function mechanism, and (3) Discover novel GPCR variants and integrate genetics with functional mutagenesis to define mechanisms of disease. Overall, we propose to combine genetics and structural biology approaches to expand on a foundation for pharmacologic strategies targeting GPCRs in autoimmune disease.