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Vol. 53, Issue 6, 981-990, June 1998
: Evidence for
Intramolecular Signal Transduction
Departments of
Cellular and Molecular Physiology (G.G., C.H.B.) and
Pharmacology (S.R.M.), Yale University School of Medicine, New Haven,
Connecticut 06520-8026, and
Department of Psychiatry and Center for
Neurobiology and Psychiatry (P.T.W.), University of California, San
Francisco, California 94143
To investigate the mechanism by which cell surface receptors activate
heterotrimeric G proteins, we applied a scanning mutagenesis approach
to the carboxyl-terminal 40% of 
s (residues 236-394) to identify residues that play a role in receptor-mediated activation. We identified four regions of sequence in which mutations significantly impaired receptor-dependent stimulation of cAMP synthesis in
transiently transfected cyc
S49 lymphoma
cells, which lack endogenous s. Residues at the carboxyl
terminus are likely to be receptor contact sites. Buried residues near
the bound GDP are connected to the carboxyl terminus by an helix
and may regulate GDP affinity. Residues in two adjacent loops of the
GTPase domain at the interface with the helical domain, one of which
includes a region, switch III, that changes conformation on GTP
binding, are positioned to relay the receptor-initiated signal across
the domain interface to facilitate GDP release. Consistent with this
hypothesis, replacing the helical domain of s with that
of i2 in an
s/i2/s chimera corrects
the defect in receptor-mediated activation caused by i2
substitutions on the GTPase side of the interface. Thus, complementary
interactions between residues across the domain interface seem to play
a role in receptor-catalyzed activation.
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