Activator of G protein signaling 3 is a guanine dissociation inhibitor for gα subunits

Luc De Vries, Thierry Fischer, Hélène Tronchère, Greg M. Brothers, Bentley Strockbine, David P. Siderovski, Marilyn Gist Farquhar

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

Abstract

Activator of G protein signaling 3 (AGS3) is a newly identified protein shown to act at the level of the G protein itself. AGS3 belongs to the GoLoco family of proteins, sharing the 19-aa GoLoco motif that is a Gαi/o binding motif. AGS3 interacts only with members of the Gαi/o subfamily, By surface plasmon resonance, we found that AGS3 binds exclusively to the GDP-bound form of Gαi3. In GTPγS binding assays, AGS3 behaves as a guanine dissociation inhibitor (GDI), inhibiting the rate of exchange of GDP for GTP by Gαi3. AGS3 interacts with both Gαi3 and Gαo subunits, but has GDI activity only on Geαi3, not on Gαo. The fourth GoLoco motif of AGS3 is a major contributor to this activity. AGS3 stabilizes Gαi/3 in its GDP-bound form, as it inhibits the increase in tryptophan fluorescence of the Gαi3-GDP subunit stimulated by AIF4/-. AGS3 is widely expressed as it is detected by immunoblotting in brain, testis, liver, kidney, heart, pancreas, and in PC-12 cells. Several different sizes of the protein are detected. By Northern blotting, AGS3 shows 2.3-kb and 3.5-kb mRNAs in heart and brain, respectively, suggesting tissue-specific alternative splicing. Taken together, our results demonstrate that AGS3 is a GDI. To the best of our knowledge, no other GDI has been described for heterotrimeric G proteins. Inhibition of the Gα subunit and stimulation of heterotrimeric G protein signaling, presumably by stimulating Gβγ, extend the possibilities for modulating signal transduction through heterotrimeric G proteins.

Original languageEnglish
Pages (from-to)14364-14369
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number26
DOIs
StatePublished - 19 Dec 2000

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