DAPLE protein inhibits nucleotide exchange on Gαs and Gαq via the same motif that activates Gαi

Arthur Marivin, Marcin Maziarz, Jingyi Zhao, Vincent DiGiacomo, Isabel Olmos Calvo, Emily A. Mann, Jason Ear, Juan B. Blanco-Canosa, Elliott M. Ross, Pradipta Ghosh, Mikel Garcia-Marcos

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 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 Gi/o family (Gαi) 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 Gαs and inhibits nucleotide exchange. The G-protein specificity of DAPLE and how it might affect nucleotide exchange on G proteins besides Gαi remain to be investigated. Here, we show that DAPLE’s GBA motif, in addition to Gαi, binds efficiently to members of the Gs and Gq/11 families (Gαs and Gαq, respectively), but not of the G12/13 family (Gα12) 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 Gαs and Gαq. Unlike the nucleotide-exchange acceleration observed for Gαi, DAPLE inhibited nucleotide exchange on Gαs and Gαq. 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.

Original languageEnglish (US)
Pages (from-to)2270-2284
Number of pages15
JournalJournal of Biological Chemistry
Volume295
Issue number8
DOIs
StatePublished - Feb 21 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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