CRBM, Université de Montpellier, CNRS, 1919 Route de Mende, CEDEX 5, 34293 Montpellier, France.
Institute of Biophysics, ANAS, Baku AZ1141, Azerbaijan.
Biomolecules. 2022 Nov 1;12(11):1610. doi: 10.3390/biom12111610.
Alternative splicing is an important means of generating the protein diversity necessary for cellular functions. Hence, there is a growing interest in assessing the structural and functional impact of alternative protein isoforms. Typically, experimental studies are used to determine the structures of the canonical proteins ignoring the other isoforms. Therefore, there is still a large gap between abundant sequence information and meager structural data on these isoforms. During the last decade, significant progress has been achieved in the development of bioinformatics tools for structural and functional annotations of proteins. Moreover, the appearance of the AlphaFold program opened up the possibility to model a large number of high-confidence structures of the isoforms. In this study, using state-of-the-art tools, we performed in silico analysis of 58 eukaryotic proteomes. The evaluated structural states included structured domains, intrinsically disordered regions, aggregation-prone regions, and tandem repeats. Among other things, we found that the isoforms have fewer signal peptides, transmembrane regions, or tandem repeat regions in comparison with their canonical counterparts. This could change protein function and/or cellular localization. The AlphaFold modeling demonstrated that frequently isoforms, having differences with the canonical sequences, still can fold in similar structures though with significant structural rearrangements which can lead to changes of their functions. Based on the modeling, we suggested classification of the structural differences between canonical proteins and isoforms. Altogether, we can conclude that a majority of isoforms, similarly to the canonical proteins are under selective pressure for the functional roles.
可变剪接是产生细胞功能所需蛋白质多样性的重要手段。因此，人们越来越感兴趣于评估替代蛋白质异构体的结构和功能影响。通常，使用实验研究来确定规范蛋白质的结构而忽略其他异构体。因此，在这些异构体的丰富序列信息和稀缺结构数据之间仍然存在很大差距。在过去的十年中，在开发用于蛋白质结构和功能注释的生物信息学工具方面取得了重大进展。此外，AlphaFold 程序的出现为大量高置信度异构体模型的构建开辟了可能性。在这项研究中，我们使用最先进的工具对 58 种真核生物蛋白质组进行了计算机分析。评估的结构状态包括结构域、固有无序区、聚集倾向区和串联重复区。除其他外，我们发现与规范物相比，异构体的信号肽、跨膜区或串联重复区更少。这可能会改变蛋白质的功能和/或细胞定位。AlphaFold 建模表明，经常与规范序列存在差异的异构体仍然可以在类似的结构中折叠，尽管存在显著的结构重排，这可能导致其功能发生变化。基于建模，我们提出了规范蛋白和异构体之间结构差异的分类。总的来说，我们可以得出结论，大多数异构体与规范蛋白一样，受到功能作用的选择性压力。
