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AH Cheung, RR Huang and CD Strader
Department of Molecular Pharmacology and Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
Mutagenesis and biochemical analysis have indicated that amino acid residues at the amino terminus of the third intracellular loops of guanine nucleotide-binding protein (G protein)-coupled receptors are important in mediating the coupling of the receptors to G proteins. Because the primary sequence of this region is not conserved among all receptors that couple to the same G protein, it has been suggested that some other physicochemical property of this domain may determine G protein activation. To determine the relative contributions of charge distribution and amino acid side chain interactions within this domain of the beta-adrenergic receptor (beta AR) to the activation of the G protein Gs, point mutations were introduced into this region of the beta AR. Replacement of all four of the basic amino acid residues within this region (amino acids 222-236) with serine residues had a negligible effect on the ability of the beta AR to activate Gs. In contrast, replacement of the hydrophobic amino acids within this same region with leucine residues resulted in a mutant receptor that was poorly coupled to Gs. These results suggest that specific hydrophobic interactions within this region of the receptor may play a more significant role than ionic or hydrophilic interactions in mediating G protein activation.
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