The N-terminal Extension of Gα_q Is Critical for Constraining the Selectivity of Receptor Coupling*

Abstract

Characteristically, an individual member of the superfamily of G protein-coupled receptors can interact only with a limited number of the many structurally closely related G protein heterotrimers that are expressed within a cell. Interestingly, the N termini of two G protein α subunits, Gα_q and Gα₁₁, differ from those of other α subunits in that they display a unique, highly conserved six-amino acid extension. To test the hypothesis that this sequence element is critical for proper receptor recognition, we prepared a Gα_q deletion mutant (−6q) lacking these first six amino acids. The −6q construct (or wild type Gα_q as a control) was coexpressed (in COS-7 cells) with several different G_i/o- or G_s-coupled receptors, and ligand-induced increases in inositol phosphate production were determined as a measure of G protein activation. Whereas these receptors did not efficiently interact with wild type Gα_q, most of them gained the ability to productively couple to −6q. Additional experiments indicated that the observed functional promiscuity of −6q is not due to overexpression (as compared with wild type Gα_q) or to a lack of palmitoylation. We conclude that the N-terminal extension characteristic for Gα_q/11 proteins is critical for constraining the receptor coupling selectivity of these subunits, indicative of a novel mechanism by which the fidelity of receptor-G protein interactions can be regulated.