Interdisciplinary Initiatives Program Round 11 - 2022
Georgios Skiniotis, Molecular & Cellular Physiology, Structural Biology, and Photon Science Directorate
Alexander Dunn, Chemical Engineering
Adhesion G protein-coupled receptors (aGPCRs) belong to a unique class of cell surface receptors that signal upon stimulation by adhesive interactions with neighboring cells or the extracellaulr matrix. These receptors play crucial roles in regulating cell adhesion, migration, cycle, cell death and differentiation. aGPCRs are associated with dysplasia and tumorigenesis, with cancer-associated mutations or changes in expression levels found among multiple receptors in this group. Furthermore, aGPCR adhesive interactions and activation play fundamental roles in early nervous system development, and mutations in aGPCRs contribute to numerous neurological diseases. Notwithstanding their importance, the molecular mechanisms driving aGPCR activation remain unclear and are hotly debated. In this project we will use single-molecule biophysical assays to monitor the activation of aGPCRs reconstituted in membrane islands as a function of ligand concentration, clustering, and mechanical stimulation. If fully successful, this work will greatly advance our understanding of this enigmatic class of receptor proteins, knowledge that is critical for the development of therapeutic strategies targeting aGCPRs involved in cancer and neurological disorders.