Studer Romain A, Opperdoes Fred R, Nicolaes Gerry A F, Mulder André B, Mulder René
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Laboratory of Biochemistry, de Duve Institute and Université catholique de Louvain, Brussels 1200, Belgium.
Open Biol. 2014 Oct;4(10). doi: 10.1098/rsob.140121.
Although protein S (PROS1) and growth arrest-specific protein 6 (GAS6) proteins are homologous with a high degree of structural similarity, they are functionally different. The objectives of this study were to identify the evolutionary origins from which these functional differences arose. Bioinformatics methods were used to estimate the evolutionary divergence time and to detect the amino acid residues under functional divergence between GAS6 and PROS1. The properties of these residues were analysed in the light of their three-dimensional structures, such as their stability effects, the identification of electrostatic patches and the identification potential protein-protein interaction. The divergence between GAS6 and PROS1 probably occurred during the whole-genome duplications in vertebrates. A total of 78 amino acid sites were identified to be under functional divergence. One of these sites, Asn463, is involved in N-glycosylation in GAS6, but is mutated in PROS1, preventing this post-translational modification. Sites experiencing functional divergence tend to express a greater diversity of stabilizing/destabilizing effects than sites that do not experience such functional divergence. Three electrostatic patches in the LG1/LG2 domains were found to differ between GAS6 and PROS1. Finally, a surface responsible for protein-protein interactions was identified. These results may help researchers to analyse disease-causing mutations in the light of evolutionary and structural constraints, and link genetic pathology to clinical phenotypes.
尽管蛋白S（PROS1）和生长停滞特异性蛋白6（GAS6）在结构上高度同源，但它们的功能却有所不同。本研究的目的是确定这些功能差异产生的进化起源。采用生物信息学方法估计进化分歧时间，并检测GAS6和PROS1之间功能分歧下的氨基酸残基。根据这些残基的三维结构分析其特性，如稳定性效应、静电斑块的识别以及潜在蛋白质-蛋白质相互作用的识别。GAS6和PROS1之间的分歧可能发生在脊椎动物全基因组复制期间。共鉴定出78个氨基酸位点存在功能分歧。其中一个位点，Asn463，参与GAS6的N-糖基化，但在PROS1中发生突变，阻止了这种翻译后修饰。经历功能分歧的位点比未经历这种功能分歧的位点倾向于表现出更大的稳定/不稳定效应多样性。发现GAS6和PROS1的LG1/LG2结构域中有三个静电斑块不同。最后，确定了一个负责蛋白质-蛋白质相互作用的表面。这些结果可能有助于研究人员根据进化和结构限制分析致病突变，并将遗传病理学与临床表型联系起来。
