Ancient thioredoxins evolved to modern-day stability-function requirement by altering native state ensemble
Ancient thioredoxins evolved to modern-day stability-function requirement by altering native state ensemble
复制标题
DOI：
10.1098/rstb.2017.0184
复制
发表时间：
2018-06-19
影响因子：
6.3
通讯作者：
Ozkan, S. Banu
中科院分区：
文献类型：
--
作者：
Modi, Tushar;Huihui, Jonathan;Ozkan, S. Banu
硫氧还蛋白（THRXs）-减少其他蛋白质的小球状蛋白质-在所有形式的生命中普遍存在，从哺乳动物到海洋。虽然祖先硫氧还蛋白与现代（现存）同源物具有序列和结构相似性，但它们表现出显着不同的功能活性和稳定性。我们通过对它们（古代和现代THRX）的天然状态集合的比较研究来研究这个难题，这些集合由动态柔性指数（DFI）量化，动态柔性指数是一种衡量氨基酸对蛋白质其余部分扰动的相对弹性的指标。使用DFI图谱对蛋白质进行聚类非常类似于基于其活性和稳定性的替代分类方案。现存蛋白质的DFI谱在α 3、α 4螺旋和催化区域周围是显著不同的。同样，变构偶联的活性位点与其余的蛋白质是不同的古代和现存的THRXs，可能解释了在低pH值的催化活性降低与进化。在全球范围内，我们注意到，人口的低灵活性（称为铰链）和高灵活性的网站随着进化而增加。DFI分布的异质性（用方差量化）随着熔融温度的降低而增加，这通常与古代蛋白质向现代蛋白质的进化有关。本文是“Allostery和分子机器”讨论会的一部分。
Thioredoxins (THRXs)-small globular proteins that reduce other proteins-are ubiquitous in all forms of life, from Archaea to mammals. Although ancestral thioredoxins share sequential and structural similarity with the modern-day (extant) homologues, they exhibit significantly different functional activity and stability. We investigate this puzzle by comparative studies of their (ancient and modern-day THRXs') native state ensemble, as quantified by the dynamic flexibility index (DFI), a metric for the relative resilience of an amino acid to perturbations in the rest of the protein. Clustering proteins using DFI profiles strongly resemble an alternative classification scheme based on their activity and stability. The DFI profiles of the extant proteins are substantially different around the alpha 3, alpha 4 helices and catalytic regions. Likewise, allosteric coupling of the active site with the rest of the protein is different between ancient and extant THRXs, possibly explaining the decreased catalytic activity at lowp Hwith evolution. At a global level, we note that the population of low-flexibility (called hinges) and high-flexibility sites increases with evolution. The heterogeneity (quantified by the variance) in DFI distribution increases with the decrease in the melting temperature typically associated with the evolution of ancient proteins to their modern-day counterparts.This article is part of a discussion meeting issue 'Allostery and molecular machines'.