ConSurf: An algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information
ConSurf: An algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information
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DOI：
10.1006/jmbi.2000.4474
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发表时间：
2001-03-16
影响因子：
5.6
通讯作者：
Ben-Tal, N
中科院分区：
文献类型：
--
作者：
Armon, A;Graur, D;Ben-Tal, N
鉴定蛋白质表面功能重要区域的实验方法涉及诱变，其中暴露的残基被一个接一个地替换，同时记录与其他蛋白质结合的变化或活性的变化。然而，实际的考虑限制了这些方法的使用，小规模的研究，排除了蛋白质表面上的所有功能上重要的残基的完整映射。我们在这里提出了一种替代方法，涉及使用的进化数据的形式的多序列比对的蛋白质家族，以确定热点和表面补丁，可能是在与其他蛋白质，结构域，肽，DNA，RNA或配体接触。这种方法的基本假设是，对结合重要的关键残基应该在整个进化过程中保持不变，就像对维持蛋白质折叠至关重要的残基一样，即埋藏残基。这种方法的实施中的主要限制是蛋白质家族的序列空间可能被不均匀地采样，例如哺乳动物可能被过度表示。因此，在比对中看似保守的位置可能反映分类学上不均匀的采样，而不是指示结构或功能重要性。为了避免这个问题，我们在这里提出了一种新的方法的基础上，蛋白质之间的进化关系所揭示的推断系统发育树，并证明其映射结合位点的SH2和PTB信号结构域的能力。实现这些思想的计算机程序可以在http://ashtoret.tau.ac.il/上免费获得，类似于rony（C）2001学术出版社。
Experimental approaches for the identification of functionally important regions on the surface of a protein involve mutagenesis, in which exposed residues are replaced one after another while the change in binding to other proteins or changes in activity are recorded. However, practical considerations limit the use of those methods to small-scale studies, precluding a full mapping of all the functionally important residues on the surface of a protein. We present here an alternative approach involving the use of evolutionary data in the form of multiple-sequence alignment for a protein family to identify hot spots and surface patches that are likely to be in contact with other proteins, domains, peptides, DNA, RNA or ligands. The underlying assumption in this approach is that key residues that are important for binding should be conserved throughout evolution, just like residues that are crucial for maintaining the protein fold, i.e. buried residues. A main limitation in the implementation of this approach is that the sequence space of a protein family may be unevenly sampled, e.g. mammals may be overly represented. Thus, a seemingly conserved position in the alignment may reflect a taxonomically uneven sampling, rather than being indicative of structural or functional importance. To avoid this problem, we present here a novel methodology based on evolutionary relations among proteins as revealed by inferred phylogenetic trees, and demonstrate its capabilities for mapping binding sites in SH2 and PTB signaling domains. A computer program that implements these ideas is available freely at: http://ashtoret.tau.ac.il/ similar to rony (C) 2001 Academic Press.