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蛋白质内补偿性替换的结构决定因素。

The Structural Determinants of Intra-Protein Compensatory Substitutions.

机构信息

RG Molecular Systems Evolution, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, August-Thienemann-Straße 2, 24306 Plön, Germany.

Institute of Evolution Sciences of Montpellier (ISEM), CNRS, University of Montpellier, IRD, EPHE, 34095 Montpellier, France.

出版信息

Mol Biol Evol. 2022 Apr 11;39(4). doi: 10.1093/molbev/msac063.

Abstract

Compensatory substitutions happen when one mutation is advantageously selected because it restores the loss of fitness induced by a previous deleterious mutation. How frequent such mutations occur in evolution and what is the structural and functional context permitting their emergence remain open questions. We built an atlas of intra-protein compensatory substitutions using a phylogenetic approach and a dataset of 1,630 bacterial protein families for which high-quality sequence alignments and experimentally derived protein structures were available. We identified more than 51,000 positions coevolving by the mean of predicted compensatory mutations. Using the evolutionary and structural properties of the analyzed positions, we demonstrate that compensatory mutations are scarce (typically only a few in the protein history) but widespread (the majority of proteins experienced at least one). Typical coevolving residues are evolving slowly, are located in the protein core outside secondary structure motifs, and are more often in contact than expected by chance, even after accounting for their evolutionary rate and solvent exposure. An exception to this general scheme is residues coevolving for charge compensation, which are evolving faster than noncoevolving sites, in contradiction with predictions from simple coevolutionary models, but similar to stem pairs in RNA. While sites with a significant pattern of coevolution by compensatory mutations are rare, the comparative analysis of hundreds of structures ultimately permits a better understanding of the link between the three-dimensional structure of a protein and its fitness landscape.

摘要

当一个突变有利地被选择,因为它恢复了先前有害突变引起的适应性丧失时,就会发生补偿性替换。这种突变在进化中发生的频率是多少,以及允许它们出现的结构和功能背景是什么,仍然是悬而未决的问题。我们使用系统发育方法和一组 1630 个细菌蛋白质家族的数据集构建了蛋白质内补偿性替换的图谱,这些蛋白质家族具有高质量的序列比对和实验得出的蛋白质结构。我们通过预测的补偿性突变识别了超过 51000 个共进化的位置。利用分析位置的进化和结构特性,我们证明补偿性突变很少(蛋白质历史上通常只有几个)但很普遍(大多数蛋白质至少经历过一次)。典型的共进化残基进化缓慢,位于蛋白质核心,远离二级结构模体,比随机预期的接触更频繁,即使考虑到它们的进化率和溶剂暴露也是如此。这种一般模式的一个例外是用于电荷补偿的共进化残基,它们的进化速度比非共进化位点快,这与简单共进化模型的预测相矛盾,但与 RNA 中的茎对相似。虽然具有显著补偿性突变共进化模式的位点很少,但对数百个结构的比较分析最终可以更好地理解蛋白质的三维结构与其适应性景观之间的联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e761/9004419/77532ba5ebbd/msac063f1.jpg

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