Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
PLoS Comput Biol. 2023 Mar 23;19(3):e1010966. doi: 10.1371/journal.pcbi.1010966. eCollection 2023 Mar.
Despite the vast phenotypic differences observed across primates, their protein products are largely similar to each other at the sequence level. We hypothesized that, since proteins accomplish all their functions via interactions with other molecules, alterations in the sites that participate in these interactions may be of critical importance. To uncover the extent to which these sites evolve across primates, we built a structurally-derived dataset of ~4,200 one-to-one orthologous sequence groups across 18 primate species, consisting of ~68,000 ligand-binding sites that interact with DNA, RNA, small molecules, ions, or peptides. Using this dataset, we identify functionally important patterns of conservation and variation within the amino acid residues that facilitate protein-ligand interactions across the primate phylogeny. We uncover that interaction sites are significantly more conserved than other sites, and that sites binding DNA and RNA further exhibit the lowest levels of variation. We also show that the subset of ligand-binding sites that do vary are enriched in components of gene regulatory pathways and uncover several instances of human-specific ligand-binding site changes within transcription factors. Altogether, our results suggest that ligand-binding sites have experienced selective pressure in primates and propose that variation in these sites may have an outsized effect on phenotypic variation in primates through pleiotropic effects on gene regulation.
尽管灵长类动物之间存在巨大的表型差异，但它们的蛋白质产物在序列水平上彼此非常相似。我们假设，由于蛋白质通过与其他分子的相互作用来完成所有功能，因此参与这些相互作用的位点的改变可能具有至关重要的意义。为了揭示这些位点在灵长类动物中的进化程度，我们构建了一个由约 4200 个一对一直系同源序列组组成的结构衍生数据集，涵盖了 18 种灵长类动物，包含约 68000 个与 DNA、RNA、小分子、离子或肽相互作用的配体结合位点。利用这个数据集，我们在氨基酸残基中识别出了功能重要的保守和变异模式，这些模式促进了整个灵长类动物进化过程中的蛋白质-配体相互作用。我们发现，相互作用位点比其他位点显著更保守，而与 DNA 和 RNA 结合的位点进一步表现出最低的变异水平。我们还表明，在发生变异的配体结合位点中，富含基因调控途径的组成部分，并在转录因子中发现了几个人类特异性配体结合位点变化的实例。总之，我们的研究结果表明，配体结合位点在灵长类动物中经历了选择性压力，并提出这些位点的变异可能通过对基因调控的多效性对灵长类动物的表型变异产生巨大影响。
