PDF(Pubmed)
Abstract：
Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington\'s disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2\'s role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.
摘要：
Rad和宝石样GTP结合蛋白2（Rem2），Ras样GTPasesRGK家族的成员，与亨廷顿氏病和长QT综合征有关，并在大脑和内分泌细胞中高度表达。我们研究了在各种哺乳动物物种中发现的Rem2的进化史，专注于纯化选择和协同进化在塑造其序列和蛋白质结构约束中的作用。我们对175种哺乳动物的Rem2序列的分析发现，在70％的非不变密码子位点中进行了强烈的纯化选择，这是必需蛋白的特征，在生物学过程中起关键作用，并且与Rem2在调节神经元发育和功能中的作用一致。我们推断了Rem2中50对密码子位点的上位效应，其中一些预计会对人类健康产生有害影响。此外,我们使用已灭绝和现存序列的蛋白质结构预测重建了哺乳动物Rem2的祖先进化史，这揭示了改变Rem2基因序列的替换如何在维持核心功能机制的同时影响可变区蛋白质结构的动力学。通过了解选择性压力，蛋白质和基因相互作用塑造了Rem2蛋白的序列和结构，我们对其生物学和功能限制有了更深入的了解。
