Neuroscience Program, Vanderbilt University, Nashville, TN, USA.
Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
BMC Evol Biol. 2018 Apr 11;18(1):51. doi: 10.1186/s12862-018-1147-8.
Heterotrimeric G proteins are fundamental signaling proteins composed of three subunits, Gα and a Gβγ dimer. The role of Gα as a molecular switch is critical for transmitting and amplifying intracellular signaling cascades initiated by an activated G protein Coupled Receptor (GPCR). Despite their biochemical and therapeutic importance, the study of G protein evolution has been limited to the scope of a few model organisms. Furthermore, of the five primary Gα subfamilies, the underlying gene structure of only two families has been thoroughly investigated outside of Mammalia evolution. Therefore our understanding of Gα emergence and evolution across phylogeny remains incomplete.
We have computationally identified the presence and absence of every Gα gene (GNA-) across all major branches of Deuterostomia and evaluated the conservation of the underlying exon-intron structures across these phylogenetic groups. We provide evidence of mutually exclusive exon inclusion through alternative splicing in specific lineages. Variations of splice site conservation and isoforms were found for several paralogs which coincide with conserved, putative motifs of DNA-/RNA-binding proteins. In addition to our curated gene annotations, within Primates, we identified 15 retrotranspositions, many of which have undergone pseudogenization. Most importantly, we find numerous deviations from previous findings regarding the presence and absence of individual GNA- genes, nuanced differences in phyla-specific gene copy numbers, novel paralog duplications and subsequent intron gain and loss events.
Our curated annotations allow us to draw more accurate inferences regarding the emergence of all Gα family members across Metazoa and to present a new, updated theory of Gα evolution. Leveraging this, our results are critical for gaining new insights into the co-evolution of the Gα subunit and its many protein binding partners, especially therapeutically relevant G protein - GPCR signaling pathways which radiated in Vertebrata evolution.
三聚体 G 蛋白是由三个亚基组成的基本信号蛋白，包括 Gα 和一个 Gβγ 二聚体。Gα 作为分子开关的作用对于传递和放大被激活的 G 蛋白偶联受体 (GPCR) 启动的细胞内信号级联反应至关重要。尽管 G 蛋白在生化和治疗方面具有重要意义，但 G 蛋白进化的研究仅限于少数模式生物的范围。此外，在哺乳动物进化之外，仅对五个主要 Gα 亚家族中的两个家族进行了深入研究。因此，我们对 Gα 在整个系统发育中的出现和进化的理解仍然不完整。
我们通过计算在所有后生动物的主要分支上识别了每个 Gα 基因（GNA-）的存在和缺失，并评估了这些进化群中基因结构的保守性。我们通过特定谱系中的选择性剪接提供了互斥外显子包含的证据。几个基因的外显子保留和同工型的变化与 DNA-/RNA-结合蛋白的保守假定基序相吻合。除了我们精心整理的基因注释外，在灵长类动物中，我们鉴定了 15 个逆转座子，其中许多已经发生了假基因化。最重要的是，我们发现了许多与单个 GNA-基因的存在和缺失、特定门特有的基因拷贝数的细微差异、新的基因重复和随后的内含子获得和丢失事件有关的偏离先前发现的结果。
我们精心整理的注释使我们能够更准确地推断出所有后生动物的 Gα 家族成员的出现，并提出了一个新的、更新的 Gα 进化理论。利用这一点，我们的结果对于深入了解 Gα 亚基与其许多蛋白质结合伙伴的共同进化至关重要，特别是在脊椎动物进化中辐射的治疗相关 G 蛋白-GPCR 信号通路。
