Single-Molecule Characterization of Calcium-Sensing Receptor Activation
Michael is a 2nd year IBiS student in Reza Vafabakhsh's lab. He received a B.S. in Biochemistry and Molecular Biology from University of California, Santa Cruz.
G-protein coupled receptors (GPCRs) represent the largest family of transmembrane receptors with about 900 members, play crucial roles in nearly every physiological process, and they are the most common target of therapeutic drugs. The metabotropic glutamate receptors (mGluRs), the calcium-sensing receptor (CasR), and the gamma-aminobutyric acid B receptor (GABAB) belong to the class C family of GPCRs. These receptors have a similar structure, with a large extracellular domain (ECD), consisting of a ligand-binding domain and a cysteine rich domain that couples to the transmembrane domain.
CasR regulates the level of calcium - one of the most important signaling molecules. Calcium plays a role in neuronal excitability, cell differentiation and migration, and regulation of parathyroid hormone levels. This makes it an enticing drug target for the treatment of Alzheimer's Disease, metastatic cancer, fertility, hyperparathyroidism, and others. The large, dynamic nature of Class C GPCRs makes them hard to study using canonical structural biology methods, which impairs rational drug design. Using single-molecule Förster resonance energy transfer (smFRET), I am characterizing the structural dynamics and biophysical properties of CasR activation. By understanding these properties of the receptor, I hope to inform drug design by implicating domains that undergo conformational rearrangement. These pockets of flexibility are prone to be sites of allosteric regulation of CasR. This information can be used in drug discovery and design.