Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding.
Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding.
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DOI：
10.4172/jpb.1000071
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发表时间：
2009-03-21
期刊：
影响因子：
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通讯作者：
Patterson RL
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文献类型：
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作者：
Hong Y;Chalkia D;Ko KD;Bhardwaj G;Chang GS;van Rossum DB;Patterson RL
在基因组时代的主要挑战之一是注释结构/功能的大量序列信息，现在可用。事实上，大多数蛋白质序列数据库缺乏全面的注释，即使存在实验证据。此外，在结构解析和功能注释的蛋白质结构域中，这些结构域中包含的其他功能并不明显。为了增加进一步的复杂性，氨基酸序列的微小变化可能导致结构和功能的深刻变化，强调需要快速可靠的方法来分析这些类型的数据。系统发生谱提供了一种定量的方法，可以将蛋白质的结构和功能特性以及它们的进化关系联系起来。使用所有的结构解析Src同源性2（SH 2）域，我们证明了知识库可以用来创建可靠地注释脂质结合的单氨基酸系统发育概况。事实上，这些措施隔离已知的磷酸酪氨酸和疏水口袋作为整体的脂质结合功能。此外，我们确定Tec家族激酶的SH 2结构域以不同的亲和力和特异性与脂质结合。模拟导致X连锁无丙种球蛋白血症（XLA）的布鲁顿酪氨酸激酶（BTK）突变，预测这些突变会改变脂质结合，我们通过实验证实了这一点。根据这些结果，我们提出BTK的SH 3-SH 2结构域中引起XLA的突变改变了脂质结合，这可能在XLA表型中起致病作用。总的来说，我们的研究表明，脂质结合蛋白的数量被大大低估，随着进一步的发展，系统发育谱可以提供一种快速增加蛋白质序列功能注释的方法。
One of the major challenges in the genomic era is annotating structure/function to the vast quantities of sequence information now available. Indeed, most of the protein sequence database lacks comprehensive annotation, even when experimental evidence exists. Further, within structurally resolved and functionally annotated protein domains, additional functionalities contained in these domains are not apparent. To add further complication, small changes in the amino-acid sequence can lead to profound changes in both structure and function, underscoring the need for rapid and reliable methods to analyze these types of data. Phylogenetic profiles provide a quantitative method that can relate the structural and functional properties of proteins, as well as their evolutionary relationships. Using all of the structurally resolved Src-Homology-2 (SH2) domains, we demonstrate that knowledge-bases can be used to create single-amino acid phylogenetic profiles which reliably annotate lipid-binding. Indeed, these measures isolate the known phosphotyrosine and hydrophobic pockets as integral to lipid-binding function. In addition, we determined that the SH2 domain of Tec family kinases bind to lipids with varying affinity and specificity. Simulating mutations in Bruton’s tyrosine kinase (BTK) that cause X-Linked Agammaglobulinemia (XLA) predict that these mutations alter lipid-binding, which we confirm experimentally. In light of these results, we propose that XLA-causing mutations in the SH3-SH2 domain of BTK alter lipid-binding, which could play a causative role in the XLA-phenotype. Overall, our study suggests that the number of lipid-binding proteins is drastically underestimated and, with further development, phylogenetic profiles can provide a method for rapidly increasing the functional annotation of protein sequences.