Group of Bioinformatics, Institute of Protein Research, Russian Academy of Science, Pushchino, Moscow Region, Russia.
PLoS One. 2018 Nov 6;13(11):e0206941. doi: 10.1371/journal.pone.0206941. eCollection 2018.
Expansion of homo-repeats is a molecular basis for human neurological diseases. We are the first who studied the influence of homo-repeats with lengths larger than four amino acid residues on the aggregation properties of 1449683 proteins across 122 eukaryotic and bacterial proteomes. Only 15% of proteins (215481) include homo-repeats of such length. We demonstrated that RNA-binding proteins with a prion-like domain are enriched with homo-repeats in comparison with other non-redundant protein sequences and those in the PDB. We performed a bioinformatics analysis for these proteins and found that proteins with homo-repeats are on average two times longer than those in the whole database. Moreover, we are first to discover that as a rule, homo-repeats appear in proteins not alone but in pairs: hydrophobic and aromatic homo-repeats appear with similar ones, while homo-repeats with small, polar and charged amino acids appear together with different preferences. We elaborated a new complementary approach to demonstrate the influence of homo-repeats on their host protein aggregation properties. We have shown that addition of artificial homo-repeats to natural and random proteins results in intensification of aggregation properties of the proteins. The maximal effect is observed for the insertion of artificial homo-repeats with 5-6 residues, which is consistent with the minimal length of an amyloidogenic region. We have also demonstrated that the ability of proteins with homo-repeats to aggregate cannot be explained only by the presence of long homo-repeats in them. There should be other characteristics of proteins intensifying the aggregation property including such as the appearance of homo-repeats in pairs in the same protein. We are the first who elaborated a new approach to study the influence of homo-repeats present in proteins on their aggregation properties and performed an appropriate analysis of the large number of proteomes and proteins.
同源重复的扩展是人类神经疾病的分子基础。我们是第一个研究长度大于四个氨基酸残基的同源重复对 122 个真核和细菌蛋白质组中的 1449683 种蛋白质聚集特性影响的人。只有 15%的蛋白质（215481 个）包含这种长度的同源重复。我们证明，与其他非冗余蛋白质序列和 PDB 中的蛋白质相比，具有类朊结构域的 RNA 结合蛋白富含这种同源重复。我们对这些蛋白质进行了生物信息学分析，发现同源重复的蛋白质的平均长度是整个数据库中蛋白质的两倍。此外，我们首次发现，作为一种规则，同源重复通常不是单独出现，而是成对出现：疏水性和芳香族同源重复与相似的同源重复一起出现，而具有小、极性和带电氨基酸的同源重复则与不同的偏好一起出现。我们详细阐述了一种新的互补方法来证明同源重复对其宿主蛋白质聚集特性的影响。我们已经表明，向天然和随机蛋白质中添加人工同源重复会增强蛋白质的聚集特性。对于插入具有 5-6 个残基的人工同源重复，观察到最大效果，这与淀粉样蛋白区域的最小长度一致。我们还表明，具有同源重复的蛋白质的聚集能力不能仅通过它们中存在长同源重复来解释。蛋白质中存在的其他特征也会增强其聚集特性，包括在同一蛋白质中同源重复的成对出现。我们是第一个详细阐述一种新方法来研究蛋白质中存在的同源重复对其聚集特性的影响，并对大量蛋白质组和蛋白质进行适当分析的人。
