The interplay of extracellular adhesion and intracellular signaling is essential for the development of all organs such as the brain, and is a key phenomenon that is disrupted in many human diseases. Adhesion GPCRs are cell-surface molecules that are believed to mediate intercellular communication via cell-cell and cell-matrix interactions. Genetic studies suggest critical roles for adhesion GPCRs in development, immunity and especially in neurobiology (such as brain development, synapse maturation/elimination, myelination of neurons, central nervous system angiogenesis and neural tube development); and link them to numerous diseases including neurodevelopmental disorders, deafness, male infertility, schizophrenia, and immune disorders.
We are interested in understanding the mechanisms by which aGPCRs function in the brain by employing functional, structural, and protein engineering approaches to address major questions in the adhesion GPCR field. We aim to understand the stepwise mechanical details of adhesion GPCR activation that is believed to start with adhesion of a ligand to the extracellular region of the adhesion GPCR, continue with transduction of the signal from the extracellular region to the transmembrane domain via the recently discovered GAIN domain, and end with the activation of the transmembrane domain by the tethered agonist peptide. We believe our structure/function relationship studies will elucidate the mechanistic details about the components that regulate adhesion GPCR activity and reveal ways of manipulating their function.