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Vol. 57, Issue 6, 1081-1092, June 2000
in Which
Substitutions Decrease Receptor-Mediated Activation and Increase
Receptor Affinity
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 
s: the 2/
4, 3/5, and 4/6 loops. Substitutions of i2 homologs for s
residues in the 2/4 loop and alanine substitutions of residues in
the 4/6 loop do not affect activation by the
2-adrenergic receptor. However, replacement of five
s residues in the 3/5 loop region with the
homologous i2 residues decreases receptor-mediated
activation of 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 3/5 loop maps near
the second and third intracellular loops of the receptor. The effects
of the 3/5 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
3/5 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.
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