MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites.
MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites.
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DOI：
10.1074/mcp.m114.043083
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Imai K
中科院分区：
文献类型：
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作者：
Fukasawa Y;Tsuji J;Fu SC;Tomii K;Horton P;Imai K
线粒体为细胞提供众多重要功能，其功能失调会导致多种疾病。因此，获得完整的线粒体蛋白质组应是理解线粒体作用的关键一步。许多线粒体蛋白质已通过实验鉴定，但完整的清单尚未形成。为填补这一空白，人们已经开发出从氨基酸序列计算预测线粒体蛋白质的方法并广泛应用，但不幸的是，其准确性远非完美。在此我们介绍MitoFates，这是一种针对可切割的N端线粒体靶向信号（前导序列）及其切割位点的改进预测方法。MitoFates引入了新的序列特征，包括带正电的两亲性、前导序列基序以及模拟前导序列切割位点的位置权重矩阵。这些特征与经典特征（如氨基酸组成和物理化学性质）相结合，作为标准支持向量机分类器的输入。在独立测试数据上，MitoFates在检测前导序列以及预测其切割位点方面都比现有预测工具表现更好。我们使用MitoFates从42217种人类蛋白质（包括可变剪接或翻译起始变体等异构体）中寻找未被发现的线粒体蛋白质。MitoFates预测1167个基因至少有一种具有前导序列的异构体。这些基因中有580个在UniProt或基因本体论中都未被标注为线粒体相关基因。有趣的是，其中包括帕金蛋白向受损线粒体易位的候选调节因子，以及许多具有已知疾病突变的基因，这表明仔细研究MitoFates的预测结果可能有助于阐明线粒体在健康和疾病中的作用。MitoFates是开源的，并且有一个方便的网络服务器可供公众使用。
Mitochondria provide numerous essential functions for cells and their dysfunction leads to a variety of diseases. Thus, obtaining a complete mitochondrial proteome should be a crucial step toward understanding the roles of mitochondria. Many mitochondrial proteins have been identified experimentally but a complete list is not yet available. To fill this gap, methods to computationally predict mitochondrial proteins from amino acid sequence have been developed and are widely used, but unfortunately, their accuracy is far from perfect. Here we describe MitoFates, an improved prediction method for cleavable N-terminal mitochondrial targeting signals (presequences) and their cleavage sites. MitoFates introduces novel sequence features including positively charged amphiphilicity, presequence motifs, and position weight matrices modeling the presequence cleavage sites. These features are combined with classical ones such as amino acid composition and physico-chemical properties as input to a standard support vector machine classifier. On independent test data, MitoFates attains better performance than existing predictors in both detection of presequences and in predicting their cleavage sites. We used MitoFates to look for undiscovered mitochondrial proteins from 42,217 human proteins (including isoforms such as alternative splicing or translation initiation variants). MitoFates predicts 1167 genes to have at least one isoform with a presequence. Five-hundred and eighty of these genes were not annotated as mitochondrial in either UniProt or Gene Ontology. Interestingly, these include candidate regulators of parkin translocation to damaged mitochondria, and also many genes with known disease mutations, suggesting that careful investigation of MitoFates predictions may be helpful in elucidating the role of mitochondria in health and disease. MitoFates is open source with a convenient web server publicly available.