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J Biol Chem, Vol. 273, Issue 28, 17886-17892, July 10, 1998

Functional Characterization of a Series of Mutant G Protein _q Subunits Displaying Promiscuous Receptor Coupling Properties

From the Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The N termini of two G protein  subunits, _q and ₁₁, differ from those of other  subunits in that they display a unique, highly conserved six-amino acid extension (MTLESI(M)). We recently showed that an _q deletion mutant lacking these six amino acids (in contrast to wild type _q) was able to couple to several different G_s- and G_i/o-coupled receptors, apparently due to promiscuous receptor/G protein coupling (Kostenis, E., Degtyarev, M. Y., Conklin, B. R., and Wess, J. (1997) J. Biol. Chem. 272, 19107-19110). To study which specific amino acids within the N-terminal segment of _q/11 are critical for constraining the receptor coupling selectivity of these subunits, this region of _q was subjected to systematic deletion and alanine scanning mutagenesis. All mutant _q constructs (or wild type _q as a control) were coexpressed (in COS-7 cells) with the m2 muscarinic or the D2 dopamine receptors, two prototypical G_i/o-coupled receptors, and ligand-induced increases in inositol phosphate production were determined as a measure of G protein activation. Surprisingly, all 14 mutant G proteins studied (but not wild type _q) gained the ability to productively interact with the two G_i/o-linked receptors. Similar results were obtained when we examined the ability of selected mutant _q subunits to couple to the G_s-coupled 2-adrenergic receptor. Additional experiments indicated that the functional promiscuity displayed by all investigated mutant _q constructs was not due to overexpression (as compared with wild type _q), lack of palmitoylation, or initiation of translation at a downstream ATG codon (codon seven). These data are consistent with the notion that the six-amino acid extension characteristic for _q/11 subunits forms a tightly folded protein subdomain that is critical for regulating the receptor coupling selectivity of these subunits.

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