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Vol. 16, Issue 10, 4557-4571, October 2005

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G Subunit Gpa2 Recruits Kelch Repeat Subunits That Inhibit Receptor-G Protein Coupling during cAMP-induced Dimorphic Transitions in Saccharomyces cerevisiae

Toshiaki Harashima ^*, and Joseph Heitman ^* 

^* Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710

Submitted May 9, 2005; Revised June 23, 2005; Accepted July 12, 2005
Monitoring Editor: Charles Boone

All eukaryotic cells sense extracellular stimuli and activate intracellular signaling cascades via G protein-coupled receptors (GPCR) and associated heterotrimeric G proteins. The Saccharomyces cerevisiae GPCR Gpr1 and associated G subunit Gpa2 sense extracellular carbon sources (including glucose) to govern filamentous growth. In contrast to conventional G subunits, Gpa2 forms an atypical G protein complex with the kelch repeat G mimic proteins Gpb1 and Gpb2. Gpb1/2 negatively regulate cAMP signaling by inhibiting Gpa2 and an as yet unidentified target. Here we show that Gpa2 requires lipid modifications of its N-terminus for membrane localization but association with the Gpr1 receptor or Gpb1/2 subunits is dispensable for membrane targeting. Instead, Gpa2 promotes membrane localization of its associated G mimic subunit Gpb2. We also show that the Gpa2 N-terminus binds both to Gpb2 and to the C-terminal tail of the Gpr1 receptor and that Gpb1/2 binding interferes with Gpr1 receptor coupling to Gpa2. Our studies invoke novel mechanisms involving GPCR-G protein modules that may be conserved in multicellular eukaryotes.

Address correspondence to: Joseph Heitman (heitm001{at}duke.edu).

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