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Sci. Signal., 9 February 2010
Vol. 3, Issue 108, p. ec46
[DOI: 10.1126/scisignal.3108ec46]


Cell Biology Challenging the Gβ{gamma} Paradigm

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

The dogma states that heterotrimeric G proteins have two active parts: the guanine nucleotide-binding G{alpha} subunit and a dimeric subunit Gβ{gamma} composed of two proteins, the Gβ and G{gamma} subunits. Additionally, most evidence suggests that the G{alpha}β{gamma} complex with G{alpha} bound to GDP is inactive and that GTP binding to G{alpha} triggers the dissociation of the G{alpha} subunit from Gβ{gamma}, allowing each subunit to then regulate the activity of downstream effectors. The study of the mating response of the budding yeast Kluyveromyces lactis by Navarro-Olmos et al. challenges two of these established paradigms in G protein signaling. In the budding yeast Saccharomyces cerevisiae, mating pheromone triggers the conventional pathway of GTP binding to G{alpha} and separation of Gβ{gamma} from the activated complex, and Gβ{gamma} then activates the mitogen-activated protein kinase cascade to mediate the mating response. Despite structural similarities and sequence conservation and the ability to interact in a yeast two-hybrid system, the K. lactis Gβ (KlGβ) and G{gamma} (KlG{gamma}) failed to suppress the sterile phenotype of S. cerevisiae, which suggests that the pathway may be different. Knocking out KlGβ alone abolished mating. Unexpectedly, knocking out KlG{gamma} in K. lactis failed to compromise mating as long as the KlG{alpha} subunit was present, but if both KlG{alpha} and KlG{gamma} were knocked out, then mating was compromised. Thus, mating appears to require Gβ and either G{alpha} or G{gamma}, which suggests that either a G{alpha}β or a Gβ{gamma} complex may function in this pathway. The ability of KlG{gamma} and KlGβ and for KlG{alpha} and KlGβ to interact was confirmed by yeast two-hybrid assay. One role of the {gamma} subunit in the function of Gβ{gamma} complexes is recruitment of the β subunit to membranes, and in S. cerevisiae mutation of the cysteine residue that is farnesylated in G{gamma} (G{gamma}S) behaves as a dominant-negative G{gamma}. However, the equivalent mutation in K. lactis KlG{gamma} failed to inhibit mating. KlGβ was associated with the membrane fraction in cells lacking KlG{gamma} but was completely cytosolic in cells lacking both KlG{gamma} and KlG{alpha}. Adding a farnesylation motif to KlGβ partially targeted the protein to the membrane and partially rescued the mating defect in cells deficient in both KlG{gamma} and KlG{alpha}. Thus, it appears that in K. lactis, Gβ can signal without G{gamma} as long as it has a mechanism to reach the membrane.

R. Navarro-Olmos, L. Kawasaki, L. Domínguez-Ramírez, L. Ongay-Larios, R. Pérez-Molina, R. Coria, The β subunit of the heterotrimeric G protein triggers the Kluyveromyces lactis pheromone response pathway in the absence of the {gamma} subunit. Mol. Biol. Cell 21, 489–498 (2010). [Abstract] [Full Text]

Citation: N. R. Gough, Challenging the Gβ{gamma} Paradigm. Sci. Signal. 3, ec46 (2010).

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