Wee L J K, Low H M
Institute for Infocomm Research, Singapore, Singapore 138632.
Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:5534-40. doi: 10.1109/EMBC.2012.6347248.
Calpains belong to a family of calcium-dependent cysteine proteases which are implicated in a myriad of pathologies such as cancer and neurodegeneration. Despite extensive experimental studies on these proteases, our knowledge of the calpain degradome is still limited. Using a dataset of 341 unique, experimentally verified calpain cleavage sites, we conducted extensive sequence analyses and discovered novel residue propensities in the region flanking the cleavage site which could be modeled for prediction using machine learning algorithms. We have developed a series of computational models incorporating support vector machines and Bayes Feature Extraction for the prediction of calpain cleavage sites. The best models achieved AROC and accuracy scores ranging from 0.79 to 0.93 and 71% to 86% respectively when tested on independent test sets. We predicted calpain cleavage sites on proteins from the receptor tyrosine kinase family and discovered potential sites of cleavage at critical regulatory domains. The results suggest a novel role of calpains as a direct regulator of receptor tyrosine kinase activity in cell survival and cell death pathways.
钙蛋白酶属于一类钙依赖性半胱氨酸蛋白酶，它们与众多病理状况有关，如癌症和神经退行性变。尽管对这些蛋白酶进行了广泛的实验研究，但我们对钙蛋白酶降解组的了解仍然有限。利用一个包含341个独特的、经过实验验证的钙蛋白酶切割位点的数据集，我们进行了广泛的序列分析，并在切割位点侧翼区域发现了新的残基倾向，这些倾向可以用机器学习算法建模进行预测。我们开发了一系列结合支持向量机和贝叶斯特征提取的计算模型，用于预测钙蛋白酶切割位点。在独立测试集上进行测试时，最佳模型的AROC和准确率得分分别为0.79至0.93和71%至86%。我们预测了受体酪氨酸激酶家族蛋白质上的钙蛋白酶切割位点，并在关键调节域发现了潜在的切割位点。结果表明，钙蛋白酶在细胞存活和细胞死亡途径中作为受体酪氨酸激酶活性的直接调节因子具有新的作用。
