Regulatory mechanism dictating GPSM3 selectivity toward G protein-coupled receptor complex

点击翻译按钮获取中文摘要

Background: G protein-coupled receptor (GPCRs) are large allosteric machines in that they dynamically bind extracellular and intracellular ligands or proteins to form complexes that propagate conformationally restricted cellular signals. This reciprocal allosteric system is the basis of the pluridimensional and heterogenicity of GPCR signaling. GPCRs serve as catalytic activators of heterotrimeric G-proteins (G) by exchanging GTP for the bound GDP on the G subunit. This guanine nucleotide exchange factor activity is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways. Regulatory and accessory proteins fine-tune the intracellular signals transduced by controlling the signal amplitude and duration or acting as a scaffold for G protein-independent signaling. One of the most recent modes of signaling regulation was recognized from the discovery of the association between inactive Gi/o subunits and GoLoco (also called GPR) motif proteins an association that excludes reformation of the G·GDP/G inactive heterotrimer. The long-term objective of this research program is dedicated to the characterization of one of the smallest members of GPR motif proteins, called GPSM3 (G-protein signaling modulator type-3). Our previous work has shown that GPSM3 is prominently expressed in hematopoietic cells and have an important role in the onset of inflammatory diseases. A recent breakthrough showed that the complex Gi/o-GPSM3 directly coupled to GPCR and could serve as a novel signaling platform in lieu of the conventional G. These works open the door to study of new scaffolding proteins that organize specific signaling complexes controlling GPSM3-mediated GPCR functions. In the next five years, we will concentrate on specific objectives by answering those questions:Aim-1: What is the selectivity of GPSM3 toward GPCRs?Aim-2: What macromolecular organization controls GPSM3 selectivity and specificity?Together, these studies will constitute the basis for a better understanding of a novel GPCR regulator. We are confident this global functional approach will lead to the construction of a signaling network that will reveal a novel mechanism of signal propagation and regulation of GPCR with broad implication. The program presented will provide a great opportunity to train HQP using a combination of innovative tools and will be rewarding for participating HQP.