Self-activating G protein α subunits engage seven-transmembrane regulator of G protein signaling (RGS) proteins and a Rho guanine nucleotide exchange factor effector in the amoeba Naegleria fowleri.
Self-activating G protein α subunits engage seven-transmembrane regulator of G protein signaling (RGS) proteins and a Rho guanine nucleotide exchange factor effector in the amoeba Naegleria fowleri.
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DOI：
10.1016/j.jbc.2022.102167
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发表时间：
2022-08
影响因子：
4.8
通讯作者：
Siderovski, David P.
中科院分区：
文献类型：
--
作者：
Bosch, Dustin E.;Jeck, William R.;Siderovski, David P.
自由生活的福氏阿米巴原虫是原发性阿米巴脑膜脑炎的病原体，对目前的治疗方法具有高度耐药性，导致死亡率>97%。由于许多治疗方法以 G 蛋白为中心的信号转导途径为目标，进一步了解福氏奈瑟菌内 G 蛋白信号转导的功能意义应该有助于未来针对这种病原体的药物发现。在这里，我们报告福氏奈瑟菌基因组编码许多转录的 G 蛋白信号传导成分，包括 G 蛋白偶联受体、异三聚体 G 蛋白亚基、G 蛋白信号传导 (RGS) 蛋白调节因子和候选 Gα 效应蛋白。我们发现 N. fowleri Gα 亚基具有不同的核苷酸循环动力学； Nf Gα5 和 Gα7 表现出比 GTP 水解更快的核苷酸交换（即“自激活”行为）。 Nf Gα7 的晶体结构突出了其无核苷酸状态的稳定性，与其快速的核苷酸交换一致。磷酸盐结合环的变化也会导致 Gα 亚基之间的核苷酸循环差异。与植物 G 蛋白信号通路类似，福氏奈瑟菌 Gα 亚基选择性地与大型七跨膜 RGS 蛋白家族的成员结合，从而加速 GTP 水解。我们发现 Nf Gα2 和 Gα3 直接与候选 Gα 效应蛋白 RGS-RhoGEF 相互作用，类似于哺乳动物 Gα12/13 信号通路。我们证明 Nf Gα2 和 Gα3 各自通过规范的 Gα/RGS 结构域界面与 RGS-RhoGEF 结合，表明与肠道病原体溶组织内阿米巴中的 G 蛋白信号传导具有共同的进化起源。这些发现进一步阐明了 G 蛋白信号传导的演变，并确定了福氏奈瑟菌药理操作的潜在靶标。
The free-living amoeba Naegleria fowleri is a causative agent of primary amoebic meningoencephalitis and is highly resistant to current therapies, resulting in mortality rates >97%. As many therapeutics target G protein–centered signal transduction pathways, further understanding the functional significance of G protein signaling within N. fowleri should aid future drug discovery against this pathogen. Here, we report that the N. fowleri genome encodes numerous transcribed G protein signaling components, including G protein–coupled receptors, heterotrimeric G protein subunits, regulator of G protein signaling (RGS) proteins, and candidate Gα effector proteins. We found N. fowleri Gα subunits have diverse nucleotide cycling kinetics; Nf Gα5 and Gα7 exhibit more rapid nucleotide exchange than GTP hydrolysis (i.e., “self-activating” behavior). A crystal structure of Nf Gα7 highlights the stability of its nucleotide-free state, consistent with its rapid nucleotide exchange. Variations in the phosphate binding loop also contribute to nucleotide cycling differences among Gα subunits. Similar to plant G protein signaling pathways, N. fowleri Gα subunits selectively engage members of a large seven-transmembrane RGS protein family, resulting in acceleration of GTP hydrolysis. We show Nf Gα2 and Gα3 directly interact with a candidate Gα effector protein, RGS-RhoGEF, similar to mammalian Gα12/13 signaling pathways. We demonstrate Nf Gα2 and Gα3 each engage RGS-RhoGEF through a canonical Gα/RGS domain interface, suggesting a shared evolutionary origin with G protein signaling in the enteric pathogen Entamoeba histolytica. These findings further illuminate the evolution of G protein signaling and identify potential targets of pharmacological manipulation in N. fowleri.
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影响因子：
8
作者：
Garcia-Marcos, M.;Ghosh, P.;Farquhar, M. G.
通讯作者：
Farquhar, M. G.
影响因子：
14.9
作者：
Finn RD;Clements J;Arndt W;Miller BL;Wheeler TJ;Schreiber F;Bateman A;Eddy SR
通讯作者：
Eddy SR
DOI：
10.1073/pnas.0502238102
发表时间：
2005-05-03
影响因子：
11.1
作者：
Alvarez-Curto, E;Rozen, DE;Schaap, P
通讯作者：
Schaap, P
影响因子：
3.5
作者：
Grigston, Jeffery C.;Osuna, Daniel;Scheible, Wolf-Ruediger;Liu, Chenggang;Stitt, Mark;Jones, Alan M.
通讯作者：
Jones, Alan M.
影响因子：
7.3
作者：
Clement ST;Dixit G;Dohlman HG
通讯作者：
Dohlman HG