Table_2_Precise Prediction of Calpain Cleavage Sites and Their Aberrance Caused by Mutations in Cancer.xlsx

As a widespread post-translational modification of proteins, calpain-mediated cleavage regulates a broad range of cellular processes, including proliferation, differentiation, cytoskeletal reorganization, and apoptosis. The identification of proteins that undergo calpain cleavage in a site-specific manner is the necessary foundation for understanding the exact molecular mechanisms and regulatory roles of calpain-mediated cleavage. In contrast with time-consuming and labor-intensive experimental methods, computational approaches for detecting calpain cleavage sites have attracted wide attention due to their efficiency and convenience. In this study, we established a novel computational tool named DeepCalpain (http://deepcalpain.cancerbio.info/) for predicting the potential calpain cleavage sites by adopting deep neural network and the particle swarm optimization algorithm. Through critical evaluation and comparison, DeepCalpain exhibited superior performance against other existing tools. Meanwhile, we found that protein interactions could enrich the calpain-substrate regulatory relationship. Since calpain-mediated cleavage was critical for cancer development and progression, we comprehensively analyzed the calpain cleavage associated mutations across 11 cancers with the help of DeepCalpain, which demonstrated that the calpain-mediated cleavage events were affected by mutations and heavily implicated in the regulation of cancer cells. These prediction and analysis results might provide helpful information to reveal the regulatory mechanism of calpain cleavage in biological pathways and different cancer types, which might open new avenues for the diagnosis and treatment of cancers.

作为一种广泛存在的蛋白质翻译后修饰（post-translational modification），钙蛋白酶（calpain）介导的蛋白切割调控着众多细胞生物学过程，包括细胞增殖、分化、细胞骨架重排以及细胞凋亡。精准鉴定发生钙蛋白酶位点特异性切割的蛋白质，是阐明钙蛋白酶介导切割的确切分子机制与调控功能的必要基础。相较于耗时耗力的实验研究方法，用于检测钙蛋白酶切割位点的计算方法因高效便捷而受到广泛关注。本研究开发了一款名为DeepCalpain的新型计算工具（访问网址：http://deepcalpain.cancerbio.info/），通过结合深度神经网络（deep neural network）与粒子群优化算法（particle swarm optimization algorithm）来预测潜在的钙蛋白酶切割位点。经严谨评估与对比后发现，DeepCalpain的性能优于其他现有工具。与此同时，本研究发现蛋白质相互作用能够强化钙蛋白酶-底物的调控关联。鉴于钙蛋白酶介导的蛋白切割对癌症发生与发展至关重要，本研究借助DeepCalpain全面分析了11种癌症中与钙蛋白酶切割相关的突变，结果表明钙蛋白酶介导的切割事件会受突变影响，且与癌细胞的调控过程密切相关。本研究的预测与分析结果可为阐明钙蛋白酶切割在生物通路及不同癌症类型中的调控机制提供有益参考，也有望为癌症的诊断与治疗开辟新方向。