Journal
CURRENT BIOLOGY
Volume 18, Issue 3, Pages 211-215Publisher
CELL PRESS
DOI: 10.1016/j.cub.2008.01.007
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Funding
- NIGMS NIH HHS [P01 GM065533, R01 GM080739-03, R01 GM080739-02, R01 GM080739-01, R01 GM073180, GM065533, R01 GM080739] Funding Source: Medline
- NIMH NIH HHS [F31 MH081472, F31-MH081472] Funding Source: Medline
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G protein-coupled receptors (GPCRs) mediate responses to a broad range of chemical and environmental signals. In yeast, a pheromone-binding GPCR triggers events leading to the fusion of haploid cells. In general, GPCRs function as guanine-nucleotide exchange factors (GEFs); upon agonist binding, the receptor induces a conformational change in the G protein alpha subunit, resulting in exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and in signal initiation. Signaling is terminated when GTP is hydrolyzed to GDP [1]. This well-established paradigm has in recent years been revised to include new components that alter the rates of GDP release, GTP binding [2-8], and GTP hydrolysis [9, 10]. Here we report the discovery of a nonreceptor GEF, Arr4. Like receptors, Arr4 binds directly to the G protein, accelerates guanine-nucleotide exchange, and stabilizes the nucleotide-free state of the alpha subunit. Moreover, Arr4 promotes G protein-dependent cellular responses, including mitogen-activated protein kinase (MAPK) phosphorylation, new-gene transcription, and mating. In contrast to known GPCRs, however, Arr4 is not a transmembrane receptor, but rather a soluble intracellular protein. Our data suggest that intracellular proteins function in cooperation with mating pheromones to amplify G protein signaling, thereby leading to full pathway activation.
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