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J. Biol. Chem., Vol. 277, Issue 34, 30581-30590, August 23, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/34/30581    most recent M204089200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akal-Strader, A. Articles by Becker, J. M. Search for Related Content PubMed PubMed Citation Articles by Akal-Strader, A. Articles by Becker, J. M. Social Bookmarking                      What's this?

Residues in the First Extracellular Loop of a G Protein-coupled Receptor Play a Role in Signal Transduction^*

Ayça Akal-Strader, Sanjay Khare^§, Dong Xu^¶**, Fred Naider^§, and Jeffrey M. Becker^¶§§

From the  Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, the ^§ Department of Chemistry, The College of Staten Island of The City University of New York, Staten Island, New York 10314, the ^¶ Genome Science & Technology Graduate School of The University of Tennessee,  Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830, and the  Ph.D Program in Biochemistry and Chemistry, The Graduate School and University Center of The City University of New York, New York, New York 10016

The Saccharomyces cerevisiae pheromone, -factor (WHWLQLKPGQPMY), and Ste2p, its G protein-coupled receptor, were used as a model system to study ligand-receptor interaction. Cys-scanning mutagenesis on each residue of EL1, the first extracellular loop of Ste2p, was used to generate a library of 36 mutants with a single Cys residue substitution. Mutation of most residues of EL1 had only negligible effects on ligand affinity and biological activity of the mutant receptors. However, five mutants were identified that were either partially (L102C and T114C) or severely (N105C, S108C, and Y111C) compromised in signaling but retained binding affinities similar to those of wild-type receptor. Three-dimensional modeling, secondary structure predictions, and subsequent circular dichroism studies on a synthetic peptide with amino acid sequence corresponding to EL1 suggested the presence of a helix corresponding to EL1 residues 106 to 114 followed by two short -strands (residues 126 to 135). The distinctive periodicity of the five residues with a signal-deficient phenotype combined with biophysical studies suggested a functional involvement in receptor activation of a face on a 3₁₀ helix in this region of EL1. These studies indicate that EL1 plays an important role in the conformational switch that activates the Ste2p receptor to initiate the mating pheromone signal transduction pathway.

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