Origin and Evolution of the Human Bcl2-Associated Athanogene-1 (BAG-1).
Origin and Evolution of the Human Bcl2-Associated Athanogene-1 (BAG-1).
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人类 Bcl2 相关 Athanogene-1 (BAG-1) 的起源和进化。
DOI：
10.3390/ijms21249701
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发表时间：
2020-12-18
影响因子：
5.6
通讯作者：
Nikolaidis N
中科院分区：
文献类型：
--
作者：
Nguyen P;Hess K;Smulders L;Le D;Briseno C;Chavez CM;Nikolaidis N
分子伴侣，特别是70 kDa的热休克蛋白（Hsp 70），是细胞应激反应的关键协调。为了执行它们的关键功能，Hsp 70需要存在特定的辅分子伴侣，其包括含有BCL 2相关的产氧基因（BAG）结构域的核苷酸交换因子。BAG-1是这些蛋白质中的一种，其在广泛的细胞过程中起作用，包括细胞凋亡、蛋白质重折叠和降解以及肿瘤发生。然而，BAG-1蛋白的起源及其在物种之间和物种内的进化大多是未知的。本报告使用直系同源序列和单核苷酸多态性（SNP）研究了BAG-1的宏观和微观进化，以阐明进化并了解自然变异如何影响细胞应激反应。我们首先收集并分析了动物、植物和真菌中的几个BAG-1序列;绘制了内含子位置和相位;重建了染色体发生;并分析了蛋白质特征。这些数据表明，BAG-1起源于动物、植物和真菌分裂之前，但大多数现存的真菌物种已经失去了BAG-1。此外，虽然BAG-1的结构一直保持相对保守，王国特定的保守差异存在于已知功能的网站，这表明在每个王国的功能专业化。然后，我们分析了来自1000个基因组数据库的SNP，以确定人类的进化模式。这些分析揭示了SNP密度在BAG 1基因内不均匀地分布，并且在BAG结构域区域中非同义/同义SNP的比率显著高于1，这是正选择的指示。为了进一步探索这一概念，我们进行了几次生化测定，发现测试的五个突变中只有一个改变了BAG-1的主要共伴侣特性。这些数据共同表明，虽然BAG-1的辅助分子伴侣功能是高度保守的，可能可以容忍几个激进的突变，BAG-1可能已经获得了专门的和潜在的未开发的功能在进化过程中。
Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one of these proteins that function in a wide range of cellular processes, including apoptosis, protein refolding, and degradation, as well as tumorigenesis. However, the origin of BAG-1 proteins and their evolution between and within species are mostly uncharacterized. This report investigated the macro- and micro-evolution of BAG-1 using orthologous sequences and single nucleotide polymorphisms (SNPs) to elucidate the evolution and understand how natural variation affects the cellular stress response. We first collected and analyzed several BAG-1 sequences across animals, plants, and fungi; mapped intron positions and phases; reconstructed phylogeny; and analyzed protein characteristics. These data indicated that BAG-1 originated before the animals, plants, and fungi split, yet most extant fungal species have lost BAG-1. Furthermore, although BAG-1’s structure has remained relatively conserved, kingdom-specific conserved differences exist at sites of known function, suggesting functional specialization within each kingdom. We then analyzed SNPs from the 1000 genomes database to determine the evolutionary patterns within humans. These analyses revealed that the SNP density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BAG domain region, which is an indication of positive selection. To further explore this notion, we performed several biochemical assays and found that only one out of five mutations tested altered the major co-chaperone properties of BAG-1. These data collectively suggest that although the co-chaperone functions of BAG-1 are highly conserved and can probably tolerate several radical mutations, BAG-1 might have acquired specialized and potentially unexplored functions during the evolutionary process.
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影响因子：
4.6
作者：
Hess, Kyle;Oliverio, Ryan;Nikolaidis, Nikolas
通讯作者：
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