Research SummaryStructure, Function and Novel Signaling Pathways of the "Noncanonical" G Protein-Coupled Receptors
G Protein-Coupled Receptors (GPCRs) constitute the largest family of cell surface receptors in the human genome and they are the targets for about half of the currently marketed drugs. The primary structure, signaling and regulatory mechanisms of GPCRs are remarkably conserved. They are typically characterized by i) seven-transmembrane (7TM) helix architecture, ii) signaling through heterotrimeric G Proteins and iii) downregulation by β-arrestins. Strikingly however, some members of this superfamily do not signal through G proteins despite having 7TM helix architecture and robust interaction with β-arrestins. Such receptors, referred to as “non-canonical” GPCRs, represent a long-standing enigma in the field. Here, we aim to elucidate molecular and structural basis of activation and signaling of these “non-canonical” receptors. Two primary goals of this proposal are 1) structure determination of selected “non-canonical” GPCRs and 2) discovery of novel signaling pathways downstream of “non-canonical’ receptors. The outcomes of this proposal will not only reveal unprecedented insights in to a fascinating example of evolutionary divergence but also provide a direct framework for structure based drug discovery to target several human diseases. Moreover, this study should also provide a currently lacking fundamental conceptual framework to fully understand activation and signaling of entire GPCR superfamily.
Figure Legend: Legend: ß-Arrestins are multifunctional scaffold proteins which mediate conserved desensitization and non-canonical signaling by G Protein-Coupled Receptors (GPCRs), the largest class of drug targets. The figure depicts the two-step mechanism by which ß-arrestins (shown in grey) interact with a ligand activated and phosphorylated GPCR (shown in orange and phosphorylated carboxy-terminus in yellow).