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Vol. 57, Issue 6, 1081-1092, June 2000

A Surface-Exposed Region of Gsalpha in Which Substitutions Decrease Receptor-Mediated Activation and Increase Receptor Affinity

Galina Grishina and Catherine H. Berlot

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut

The mechanism by which receptors activate G proteins is unclear because a connection between the receptor and the nucleotide binding site has not been established. To investigate this mechanism, we evaluated the roles in receptor interaction of three potential receptor contact sites in alpha s: the alpha 2/beta 4, alpha 3/beta 5, and alpha 4/beta 6 loops. Substitutions of alpha i2 homologs for alpha s residues in the alpha 2/beta 4 loop and alanine substitutions of residues in the alpha 4/beta 6 loop do not affect activation by the beta 2-adrenergic receptor. However, replacement of five alpha s residues in the alpha 3/beta 5 loop region with the homologous alpha i2 residues decreases receptor-mediated activation of alpha s and increases the affinity of Gs for this receptor. The substitutions do not alter guanine nucleotide binding or hydrolysis, or activation by aluminum fluoride, indicating that the effects on receptor interaction are not due to a destabilization of the guanine-nucleotide bound state. In a model of the receptor-G protein complex, the alpha 3/beta 5 loop maps near the second and third intracellular loops of the receptor. The effects of the alpha 3/beta 5 substitutions suggest that the wild-type residues may be receptor contact sites that are optimized to ensure the reversibility of receptor-G protein interactions. Furthermore, the alpha 3/beta 5 region corresponds to an exchange factor contact site in both EF-Tu and Ras, suggesting that the mechanisms by which seven-transmembrane receptors and exchange factors catalyze nucleotide exchange may share common elements.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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