Monash Centre for Data Science, Faculty of Information Technology, Monash University, Melbourne, VIC 3800, Australia.
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia and ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC 3800, Australia.
Brief Bioinform. 2019 Mar 25;20(2):638-658. doi: 10.1093/bib/bby028.
Regulation of proteolysis plays a critical role in a myriad of important cellular processes. The key to better understanding the mechanisms that control this process is to identify the specific substrates that each protease targets. To address this, we have developed iProt-Sub, a powerful bioinformatics tool for the accurate prediction of protease-specific substrates and their cleavage sites. Importantly, iProt-Sub represents a significantly advanced version of its successful predecessor, PROSPER. It provides optimized cleavage site prediction models with better prediction performance and coverage for more species-specific proteases (4 major protease families and 38 different proteases). iProt-Sub integrates heterogeneous sequence and structural features and uses a two-step feature selection procedure to further remove redundant and irrelevant features in an effort to improve the cleavage site prediction accuracy. Features used by iProt-Sub are encoded by 11 different sequence encoding schemes, including local amino acid sequence profile, secondary structure, solvent accessibility and native disorder, which will allow a more accurate representation of the protease specificity of approximately 38 proteases and training of the prediction models. Benchmarking experiments using cross-validation and independent tests showed that iProt-Sub is able to achieve a better performance than several existing generic tools. We anticipate that iProt-Sub will be a powerful tool for proteome-wide prediction of protease-specific substrates and their cleavage sites, and will facilitate hypothesis-driven functional interrogation of protease-specific substrate cleavage and proteolytic events.
蛋白质水解的调控在许多重要的细胞过程中起着关键作用。更好地理解控制这一过程的机制的关键是确定每种蛋白酶的特定底物。为了解决这个问题，我们开发了 iProt-Sub，这是一种强大的生物信息学工具，用于准确预测蛋白酶特异性底物及其切割位点。重要的是，iProt-Sub 是其前身 PROSPER 的一个显著改进版本。它为更多物种特异性的蛋白酶（4 种主要的蛋白酶家族和 38 种不同的蛋白酶）提供了优化的切割位点预测模型，具有更好的预测性能和覆盖范围。iProt-Sub 集成了异构序列和结构特征，并使用两步特征选择过程来进一步去除冗余和不相关的特征，以提高切割位点预测的准确性。iProt-Sub 使用的特征由 11 种不同的序列编码方案编码，包括局部氨基酸序列轮廓、二级结构、溶剂可及性和天然无序性，这将允许更准确地表示大约 38 种蛋白酶的蛋白酶特异性，并训练预测模型。使用交叉验证和独立测试的基准实验表明，iProt-Sub 能够实现比几个现有通用工具更好的性能。我们预计 iProt-Sub 将成为一种强大的工具，用于全蛋白质组范围内预测蛋白酶特异性底物及其切割位点，并促进基于假设的对蛋白酶特异性底物切割和蛋白水解事件的功能研究。
