DAPLE protein inhibits nucleotide exchange on Gα s and Gα q via the same motif that activates Gαi.

Autor: Marivin A; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., Maziarz M; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., Zhao J; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., DiGiacomo V; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., Olmos Calvo I; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., Mann EA; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118., Ear J; Department of Medicine and Cellular and Molecular Medicine, University of California, San Diego, California 92093., Blanco-Canosa JB; Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain 08034., Ross EM; Department of Pharmacology, Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390., Ghosh P; Department of Medicine and Cellular and Molecular Medicine, University of California, San Diego, California 92093., Garcia-Marcos M; Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118. Electronic address: mgm1@bu.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2020 Feb 21; Vol. 295 (8), pp. 2270-2284. Date of Electronic Publication: 2020 Jan 16.
DOI: 10.1074/jbc.RA119.011648
Abstrakt: Besides being regulated by G-protein-coupled receptors, the activity of heterotrimeric G proteins is modulated by many cytoplasmic proteins. GIV/Girdin and DAPLE ( D vl- a ssociating p rotein with a high frequency of le ucine) are the best-characterized members of a group of cytoplasmic regulators that contain a Gα-binding and -activating (GBA) motif and whose dysregulation underlies human diseases, including cancer and birth defects. GBA motif-containing proteins were originally reported to modulate G proteins by binding Gα subunits of the G i/o family (Gα i ) over other families (such as G s , G q/11 , or G 12/13 ), and promoting nucleotide exchange in vitro However, some evidence suggests that this is not always the case, as phosphorylation of the GBA motif of GIV promotes its binding to Gα s and inhibits nucleotide exchange. The G-protein specificity of DAPLE and how it might affect nucleotide exchange on G proteins besides Gα i remain to be investigated. Here, we show that DAPLE's GBA motif, in addition to Gα i , binds efficiently to members of the G s and G q/11 families (Gα s and Gα q , respectively), but not of the G 12/13 family (Gα 12 ) in the absence of post-translational phosphorylation. We pinpointed Met-1669 as the residue in the GBA motif of DAPLE that diverges from that in GIV and enables better binding to Gα s and Gα q Unlike the nucleotide-exchange acceleration observed for Gα i , DAPLE inhibited nucleotide exchange on Gα s and Gα q These findings indicate that GBA motifs have versatility in their G-protein-modulating effect, i.e. they can bind to Gα subunits of different classes and either stimulate or inhibit nucleotide exchange depending on the G-protein subtype.
(© 2020 Marivin et al.)
Databáze: MEDLINE
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