PMID: 9159128May 27, 1997Paper

Conditional activation defect of a human Gsalpha mutant

Proceedings of the National Academy of Sciences of the United States of America
Taroh IiriH R Bourne

Abstract

Hormonal signals activate trimeric G proteins by promoting exchange of GTP for GDP bound to the G protein's alpha subunit (Galpha). Here we describe a point mutation that impairs this activation mechanism in the alpha subunit of Gs, producing an inherited disorder of hormone responsiveness. Biochemical analysis reveals an activation defect that is paradoxically intensified by hormonal and other stimuli. By substituting histidine for a conserved arginine residue, the mutation removes an internal salt bridge (to a conserved glutamate) that normally acts as an intramolecular hasp to maintain tight binding of the gamma-phosphate of GTP. In its basal, unperturbed state, the mutant alphas binds guanosine 5'-[gamma-thio]triphosphate (GTP[gammaS]), a GTP analog, slightly less tightly than does normal alphas, but (in the GTP[gammaS]-bound form) can stimulate adenylyl cyclase. The activation defect becomes prominent only under conditions that destabilize binding of guanine nucleotide (receptor stimulation) or impair the ability of alphas to bind the gamma-phosphate of GTP (cholera toxin, AlF4- ion). Although GDP release is usually the rate-limiting step in nucleotide exchange, the biochemical phenotype of this mutant alphas indicates tha...Continue Reading

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Citations

Apr 1, 1999·The New England Journal of Medicine·Z FarfelT Iiri
Sep 27, 2012·The Journal of Biological Chemistry·Atsuro OishiTaroh Iiri
Feb 3, 1999·Annals of the New York Academy of Sciences·S EmamiG Rosselin
Oct 27, 2007·Proceedings of the National Academy of Sciences of the United States of America·Noriko MakitaTaroh Iiri
Mar 21, 2007·Proceedings of the National Academy of Sciences of the United States of America·Noriko MakitaTaroh Iiri
Jan 20, 1999·Proceedings of the National Academy of Sciences of the United States of America·T IiriH R Bourne
May 23, 2014·Journal of Molecular Endocrinology·Kyle TurcicRobin Pals-Rylaarsdam
Oct 26, 2005·The Journal of Cell Biology·Leon FreudzonLaurinda A Jaffe
Nov 10, 2018·PLoS Computational Biology·Hongyang LiBarry J Grant
Oct 28, 2010·American Journal of Medical Genetics. Part a·Ying Fai NgaiWilliam T Gibson
Jul 17, 1998·Nature·T IiriH R Bourne
Jul 18, 2002·Annals of the New York Academy of Sciences·Lee S WeinsteinJie Liu
Jul 2, 2014·The Journal of Biological Chemistry·Anthony LeymeMikel Garcia-Marcos
Sep 14, 2004·Molecular Pharmacology·Timothy A VorthermsVal J Watts
Aug 15, 1998·The Journal of Biological Chemistry·M NatochinN O Artemyev
Apr 3, 2002·Journal of Pediatric Endocrinology & Metabolism : JPEM·Sharon H M LimKah-Yin Loke
Apr 2, 2002·Journal of Pediatric Endocrinology & Metabolism : JPEM·Zvi Farfel
Oct 24, 2018·Clinical Case Reports·Valérie LeclercqIsabelle Maystadt
Feb 27, 2021·Molecular Cell·Kevin M KnightHenrik G Dohlman
Jan 7, 1998·Science·R K SunaharaS R Sprang

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