Structural and Functional Studies of Cell-Adhesion Receptors

Project Abstract Cellular communication is essential for the development of all multicellular organisms, and is a key phenomenon that is disrupted in many human diseases. Cell-surface receptors mediate cellular communication and are the targets for 50% of FDA-approved drugs, highlighting their disease relevance and druggability. However, many cell-surface receptors remain understudied and undrugged. The research proposed in this application is focused on two families of such receptors, adhesion G Protein-Coupled Receptors (aGPCRs), and teneurins. The structures, mechanisms of action and disease relevance of these two receptor families remain largely unknown; as their large size and complex biochemical nature has made them difficult to study. Recent genetic studies revealed that aGPCRs and teneurins have essential roles in development of the nervous system, skeletal system, and heart. These receptors are linked to diseases including cancer, developmental disorders, and brain malformations, raising an urgent need for mechanistic studies on aGPCRs and teneurins. My research program aims to elucidate the molecular mechanisms by which these receptors are activated, and to develop new tools to modulate their activity against relevant diseases. The research proposed in this application involves an interdisciplinary approach, integrating structural studies of these receptors and their ligands, biochemical and biophysical assays, protein engineering approaches, and functional assays. This research will build on our previous successes using this approach, which has yielded many three-dimensional structures of aGPCRs and teneurins, has revealed crucial mechanistic concepts in the field, and has allowed a better understanding of the mechanisms of action of these receptors. A major revelation from our work is that the large extracellular regions of aGPCRs and teneurins are directly involved in regulating receptor function. Despite these advances, fundamental questions remain unanswered. The ultimate goals of this proposal are to reveal how signal transduction is mediated within the domains of these large receptors, what exactly activates them under physiological conditions, how their evolution from early organisms to higher eukaryotes have changed and diversified their critical functions, and finally how, at the molecular level, we can inhibit or activate these receptors using synthetic ligands. Our structural studies will be complemented with mutagenesis, signaling assays, the use of synthetic binders to understand how the different components of these receptors control receptor function, and physiological analyses performed by collaborators that will test the relevance of the structural and functional studies. We expect that this research will provide critical insights into the mechanistic details of aGPCR and teneurin function that will be highly informative for the development of future therapeutics; we will also produce potent and selective synthetic ligands which can serve as tools for the scientific community to study aGPCRs and teneurins.