G Proteins New Partners of Gα

Haploid and diploid yeast can exist as two different phenotypes depending on nutrient status: haploid cells can be induced to become invasive and diploid cells can be induced to undergo filamentous differentiation. Both of these processes are controlled by the G protein-coupled receptor (GPCR) Gpr1 and its cognate Gα partner Gpa2. However, there has been no evidence for the involvement of Gβ or G subunits in this signaling process. Harashima and Heitman used two hybrid analysis and biochemical assays to show that Gpa2 interacted with novel proteins called Gpb1, Gpb2, and Gpg1. The interaction between Gpg1 and Gpa2 required either Gpb1 or Gpb2, suggesting an indirect interaction. Furthermore, Gpb1 and Gpb2 preferentially bound the guanosine diphosphate form of Gpa2 in vitro, similar to the interactions between classical Gα and Gβ subunits. Analysis of the phenotypes of yeast with mutations in various players in this pathway, Gpa2, Gpr1, Gpb1, Gpb2, Gpg1, and the downstream signaling element, Tpk2, a protein kinase A catalytic subunit, suggested that Gpb1 and Gpb2 serve as redundant negative inhibitors of signaling through this pathway. Deletion of Gpb1 or Gpb2 produced yeast with hyperfilamentous growth, hyperinvasive growth, and hyperactivation of adenosine 3',5'-monophosphate (cAMP) signaling resulting in an abnormal response to nitrogen deprivation. Although the Gpb1 and Gpb2 are not homologous to classical Gβ subunits at the level of primary amino acid sequence, they may have a similar overall structure. Gpb1 and Gpb2 contain seven kelch repeats, which in another seven kelch-domain protein adopt a structure very similar to the WD-40-mediated seven-bladed β propeller of the Gβ subunits. Thus, Harashima and Heitman propose that convergent evolution has resulted in Gβ structural mimics that can couple to Gα to modulate GPCR-mediated signaling in response to nutrients in yeast.

T. Harashima, J. Heitman, The Gα protein Gpa2 controls yeast differentiation by interacting with kelch repeat proteins that mimic Gβ subunits. Mol. Cell 10, 163-173 (2002). [Online Journal]