Double suppression of the Gα protein activity by RGS proteins.

Details

Serval ID
serval:BIB_4D8AD3519992
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Double suppression of the Gα protein activity by RGS proteins.
Journal
Molecular Cell
Author(s)
Lin C., Koval A., Tishchenko S., Gabdulkhakov A., Tin U., Solis G.P., Katanaev V.L.
ISSN
1097-4164 (Electronic)
ISSN-L
1097-2765
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
53
Number
4
Pages
663-671
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis on G protein α subunits, restricting their activity downstream from G protein-coupled receptors. Here we identify Drosophila Double hit (Dhit) as a dual RGS regulator of Gαo. In addition to the conventional GTPase-activating action, Dhit possesses the guanine nucleotide dissociation inhibitor (GDI) activity, slowing the rate of GTP uptake by Gαo; both activities are mediated by the same RGS domain. These findings are recapitulated using homologous mammalian Gαo/i proteins and RGS19. Crystal structure and mutagenesis studies provide clues into the molecular mechanism for this unprecedented GDI activity. Physiologically, we confirm this activity in Drosophila asymmetric cell divisions and HEK293T cells. We show that the oncogenic Gαo mutant found in breast cancer escapes this GDI regulation. Our studies identify Dhit and its homologs as double-action regulators, inhibiting Gαo/i proteins both through suppression of their activation and acceleration of their inactivation through the single RGS domain.
Keywords
5' Untranslated Regions, Amino Acid Sequence, Animals, Breast Neoplasms/metabolism, Crystallography, X-Ray, Drosophila Proteins/metabolism, Drosophila melanogaster, Female, GTP-Binding Protein alpha Subunits/metabolism, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Guanosine Triphosphate/chemistry, HEK293 Cells, Humans, Hydrolysis, Molecular Sequence Data, Mutation, Open Reading Frames, Protein Structure, Tertiary, RGS Proteins/metabolism, Signal Transduction, Time Factors
Pubmed
Web of science
Open Access
Yes
Create date
10/10/2016 10:34
Last modification date
20/10/2020 8:19
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