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Proc Natl Acad Sci U S A

Title:		Mutation of Pro-258 in transmembrane domain 6 constitutively activates the G protein-coupled alpha-factor receptor
Author(s):		Konopka JB; Margarit SM; Dube P;
Address:		"Department of Molecular Genetics, State University of New York, Stony Brook 11794-5222, USA"
Journal Title:		Proc Natl Acad Sci U S A
Year:		1996
Volume:		93
Issue:		13
Page Number:		6764 - 6769
DOI:		10.1073/pnas.93.13.6764
ISSN/ISBN:		0027-8424 (Print) 1091-6490 (Electronic) 0027-8424 (Linking)
Abstract:		"The alpha-factor pheromone receptor stimulates MATa yeast cells to undergo conjugation. The receptor contains seven transmembrane domains that function in ligand binding and in transducing a signal to the cytoplasmic receptor sequences to mediate G protein activation. A genetic screen was used to isolate receptor mutations that constitutively signal in the absence of alpha-factor. The Pro-258-->Leu (P258L) mutation caused constitutive receptor signaling that was equivalent to about 45% of the maximum level observed in wild-type cells stimulated with alpha-factor. Mutations of both Pro-258 and the adjacent Ser-259 to Leu increased constitutive signaling to > or = 90% of the maximum level. Since Pro-258 occurs in the central portion of transmembrane domain 6, and since proline residues are expected to cause a kink in alpha-helical domains, the P258L mutation is predicted to alter the structure of transmembrane domain 6. The P258L mutation did not result in a global distortion of receptor structure because alpha-factor bound to the mutant receptors with high affinity and induced even higher levels of signaling. These results suggest that sequences surrounding Pro-258 may be involved in ligand activation of the receptor. Conformational changes in transmembrane domain 6 may effect a change in the adjacent sequences in the third intracellular loop that are thought to function in G protein activation. Greater than 90% of all G protein-coupled receptors contain a proline residue at a similar position in transmembrane domain 6, suggesting that this aspect of receptor activation may be conserved in other receptors"
Keywords:		"Amino Acid Sequence Cell Division GTP-Binding Proteins/*metabolism Genes, Dominant Mating Factor Membrane Proteins/genetics/*metabolism Molecular Sequence Data Morphogenesis Mutagenesis *Mutation Peptides/metabolism Pheromones/metabolism Proline/genetics/;"
Notes:		"MedlineKonopka, J B Margarit, S M Dube, P eng Research Support, Non-U.S. Gov't 1996/06/25 Proc Natl Acad Sci U S A. 1996 Jun 25; 93(13):6764-9. doi: 10.1073/pnas.93.13.6764"