The role of disordered regions in GPCR‐G protein signaling

Abstract

G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signaling molecules such as hormones and neurotransmitters and are the targets of several prescribed drugs. The ~800 human GPCRs allosterically activate 16 G proteins and trigger GDP release to regulate intracellular signaling. In this presentation, I will present our findings on the allosteric mechanism governing Gα activation and the determinants of selective coupling between receptors and G proteins. In the first part of the talk, I will present evidence, which suggests that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Through comparison of Gα with the small G protein Ras, we found that the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity [1]. In the second part of the talk, I will present the existence of a selectivity barcode (i.e., patterns of amino acids) within the disordered tail of each of the 16 human G proteins that is recognized by distinct regions on the ~800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs, specifically, the disordered intracellular loops allows the identification of these selectivity-determining residues [2]. These observations might explain how the GPCR-Gα system diversified rapidly while conserving the allosteric activation mechanism and provides a framework for understanding the molecular basis of coupling selectivity within individual receptors and G proteins. Support or Funding Information Medical Research Council (MC_U105185859) GPCR-G protein interface This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.