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RSS FeedsDAPLE protein inhibits nucleotide exchange on G{alpha}s and G{alpha}q via the same motif that activates G{alpha}i [Signal Transduction] (Journal of Biological Chemistry)

 
 

21 february 2020 10:03:06

 
DAPLE protein inhibits nucleotide exchange on G{alpha}s and G{alpha}q via the same motif that activates G{alpha}i [Signal Transduction] (Journal of Biological Chemistry)
 


Besides being regulated by G-protein-coupled receptors, the activity of heterotrimeric G proteins is modulated by many cytoplasmic proteins. GIV/Girdin and DAPLE (Dvl-associating protein with a high frequency of leucine) are the best-characterized members of a group of cytoplasmic regulators that contain a G?-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 G? subunits of the Gi/o family (G?i) over other families (such as Gs, Gq/11, or G12/13), 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 G?s and inhibits nucleotide exchange. The G-protein specificity of DAPLE and how it might affect nucleotide exchange on G proteins besides G?i remain to be investigated. Here, we show that DAPLE`s GBA motif, in addition to G?i, binds efficiently to members of the Gs and Gq/11 families (G?s and G?q, respectively), but not of the G12/13 family (G?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 G?s and G?q. Unlike the nucleotide-exchange acceleration observed for G?i, DAPLE inhibited nucleotide exchange on G?s and G?q. These findings indicate that GBA motifs have versatility in their G-protein-modulating effect, i.e. they can bind to G? subunits of different classes and either stimulate or inhibit nucleotide exchange depending on the G-protein subtype.


 
171 viewsCategory: Biochemistry
 
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