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J. Biol. Chem., Vol. 281, Issue 30, 20698-20714, July 28, 2006

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Oligomerization of the Yeast -Factor Receptor

IMPLICATIONS FOR DOMINANT NEGATIVE EFFECTS OF MUTANT RECEPTORS^*

Austin U. Gehret, Anshika Bajaj, Fred Naider¹, and Mark E. Dumont²

From the Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 and Department of Chemistry, College of Staten Island, City University of New York, New York, New York 10314

Oligomerization of G protein-coupled receptors is commonly observed, but the functional significance of oligomerization for this diverse family of receptors remains poorly understood. We used bioluminescence resonance energy transfer (BRET) to examine oligomerization of Ste2p, a G protein-coupled receptor that serves as the receptor for the -mating pheromone in the yeast Saccharomyces cerevisiae, under conditions where the functional effects of oligomerization could be examined. Consistent with previous results from fluorescence resonance energy transfer (Overton, M. C., and Blumer, K. J. (2000) Curr. Biol. 10, 341–344), we detected efficient energy transfer between Renilla luciferase and a modified green fluorescent protein individually fused to truncated -factor receptors lacking the cytoplasmic C-terminal tail. In addition, the low background of the BRET system allowed detection of significant, but less efficient, energy transfer between full-length receptors. The reduced efficiency of energy transfer between full-length receptors does not appear to result from different levels of receptor expression. Instead, attachment of fluorescent reporter proteins to the full-length receptors appears to significantly increase the distance between reporters. Mutations that were previously reported to block dimerization of truncated -factor receptors reduce but do not completely eliminate BRET transfer between receptors. Dominant negative effects of mutant alleles of -factor receptors appear to be mediated by receptor oligomerization since these effects are abrogated by introduction of additional mutations that reduce oligomerization. We find that heterodimers of normal and dominant negative receptors are defective in their ability to signal. Thus, signal transduction by oligomeric receptors appears to be a cooperative process requiring an interaction between functional monomers.

Received for publication, December 22, 2005 , and in revised form, April 6, 2006.

^* This work is supported by National Institutes of Health Grants GM59357 (to M. E. D.) and GM22086 (to F. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The Leonard and Esther Kurtz Term Professor at the College of Staten Island.

² To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, P. O. Box 712, Rochester, NY 14642-0001. Tel.: 585-275-2466; Fax: 585-271-2683; E-mail: mark_dumont{at}urmc.rochester.edu.

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