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Volume 272, Number 35, Issue of August 29, 1997 pp. 21673-21676
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Communication between Switch II and Switch III of the Transducin alpha  Subunit Is Essential for Target Activation

(Received for publication, March 18, 1997, and in revised form, July 1, 1997)

Qiubo Li and Richard A. Cerione

From the Department of Pharmacology, Veterinary Medical Center, Cornell University, Ithaca, New York 14853-6401

Comparisons of the tertiary structures of the GDP-bound and guanosine 5'-O-(thiotriphosphate) (GTPgamma S)-bound forms of the alpha subunit of transducin (alpha T) indicate that there are three regions that undergo changes in conformation upon alpha T activation. Two of these regions, Switch I and Switch II, were originally identified in Ras, while Switch III appears to be unique to trimeric GTP-binding proteins (G proteins). We find that replacement of the Switch III region (aspartic acid 227 through asparagine 237) with a single alanine residue yields an alpha T subunit that fully binds and hydrolyzes GTP but no longer stimulates the activity of the cyclic GMP phosphodiesterase (PDE), the physiological target for transducin. We also show that changing glutamic acid 232 of alpha T to a leucine (E232L) had no effect on rhodopsin-stimulated GTP-GDP exchange nor on the GTP hydrolytic activity of alpha T. However, the GTPgamma S-bound form of the alpha TE232L mutant was unable to stimulate the activity of the cyclic GMP PDE. The lack of stimulation was not due to an inability of the alpha TE232L mutant to bind to the target. Taken together, these results indicate that glutamic acid 232 mediates a conformational coupling between Switch II and Switch III, which is essential for converting GTP-dependent G protein-target interactions into a stimulation of target/effector activity.


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