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Abstract
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.
Highlights
Proteolytic cleavage is one of the few irreversible posttranslational modifications
We investigate the predictive performance of support vector regression (SVR) models using different sequence encoding schemes and their combinations for cleavage site prediction of multiple proteases, by performing 5-fold cross-validation
The difficult cases include cleavage site prediction of the MMP family and other proteases whose activities are regulated by confounding factors such as the presence of exosites [120,121,122]
Summary
Proteolytic cleavage is one of the few irreversible posttranslational modifications It plays a key role in numerous developmental and physiological processes, including digestion, protein degradation, endocrine signaling and cell division [1]. This process is controlled by proteases ( known as peptidases or proteinases) that selectively cleave the peptide bonds between amino acids in specific protein or peptide substrates. Through the highly selective proteolytic processing, proteases can precisely regulate a myriad of biological processes across all living organisms [1] These are many other proteases involved in protein degradation rather than processing, for example cathepsin D and cathepsin B. Proteases can function as part of an extensive network of proteolytic interactions through interacting with other important signaling pathways involving other protein substrates and enzymes, termed the ‘protease web’ [9]
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