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.

中文翻译：

---

DAPLE蛋白通过激活Gαi的相同基序抑制Gαs和Gαq上的核苷酸交换。

除了受G蛋白偶联受体的调节外，异源三聚体G蛋白的活性还受到许多细胞质蛋白的调节。GIV / Girdin和DAPLE（具有高亮氨酸频率的Dvl相关蛋白）是一组胞质调节剂中最有特色的成员，这些调节剂包含Gα结合和激活（GBA）基序，其失调是人类疾病的基础，包括癌症和先天缺陷。最初报道含GBA基序的蛋白通过结合其他家族（例如Gs，Gq / 11或G12 / 13）上的Gi / o家族（Gαi）的Gα亚基来调节G蛋白，并促进体外核苷酸交换。 ，一些证据表明情况并非总是如此，因为GIV的GBA基序的磷酸化促进了其与Gαs的结合并抑制了核苷酸交换。DAPLE的G蛋白特异性及其对Gαi以外G蛋白核苷酸交换的影响尚待研究。在这里，我们显示，除了Gαi外，DAPLE的GBA母题还可以有效地与Gs和Gq / 11家族成员（分别为Gαs和Gαq）结合，而在没有帖子的情况下不与G12 / 13家族成员（Gα12）结合-翻译磷酸化。我们将Met-1669定位为DAPLE的GBA基序中的残基，该残基不同于GIV中的残基，并能够更好地与Gαs和Gαq结合。与观察到的Gαi核苷酸交换加速不同，DAPLE抑制了Gαs和Gαq的核苷酸交换。这些发现表明： GBA基序在其G蛋白调节作用中具有多功能性，即它们可以与不同类别的Gα亚基结合，并根据G蛋白亚型刺激或抑制核苷酸交换。