Proteome-wide discovery of evolutionary conserved sequences in disordered regions.
Proteome-wide discovery of evolutionary conserved sequences in disordered regions.
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DOI：
10.1126/scisignal.2002515
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发表时间：
2012-03-13
影响因子：
7.3
通讯作者：
Moses AM
中科院分区：
文献类型：
--
作者：
Nguyen Ba AN;Yeh BJ;van Dyk D;Davidson AR;Andrews BJ;Weiss EL;Moses AM
至少有30%的人类蛋白质被认为含有内在无序的区域，缺乏稳定的结构构象。尽管缺乏酶的功能，并有很少的蛋白质结构域，无序区域是功能上重要的蛋白质调控，并含有短的线性基序（短肽序列参与蛋白质-蛋白质相互作用），但在大多数无序区域，功能氨基酸残基仍然未知。我们根据保守性表明功能残基的假设，在无序区域内搜索进化上保守的序列。使用系统发育隐马尔可夫模型（HMM），我们作出了准确的，具体的预测功能元件在无序区域，即使这些元素只有两个或三个氨基酸长。在我们发现的保守序列中，有以前已知的和新发现的短线性基序，我们通过实验验证了关键的例子，包括可能介导蛋白激酶Cbk 1与其底物之间相互作用的基序。我们还观察到，在蛋白质相互作用网络中与许多伙伴相互作用的枢纽蛋白高度富集在这些保守序列中。我们的分析使无序区域中的功能残基的系统鉴定，并建议至少5%的氨基酸在无序区域中的功能是重要的。
At least 30% of human proteins are thought to contain intrinsically disordered regions, which lack stable structural conformation. Despite lacking enzymatic functions and having few protein domains, disordered regions are functionally important for protein regulation and contain short linear motifs (short peptide sequences involved in protein-protein interactions), but in most disordered regions, the functional amino acid residues remain unknown. We searched for evolutionarily conserved sequences within disordered regions according to the hypothesis that conservation would indicate functional residues. Using a phylogenetic hidden Markov model (phylo-HMM), we made accurate, specific predictions of functional elements in disordered regions even when these elements are only two or three amino acids long. Among the conserved sequences that we identified were previously known and newly identified short linear motifs, and we experimentally verified key examples, including a motif that may mediate interaction between protein kinase Cbk1 and its substrates. We also observed that hub proteins, which interact with many partners in a protein interaction network, are highly enriched in these conserved sequences. Our analysis enabled the systematic identification of the functional residues in disordered regions and suggested that at least 5% of amino acids in disordered regions are important for function.