An evolutionarily conserved network of amino acids mediates gating in voltage-dependent potassium channels

被引:49
|
作者
Fleishman, SJ
Yifrach, O
Ben-Tal, N [1 ]
机构
[1] Tel Aviv Univ, Dept Biochem, George S Wise Fac Life Sci, IL-69978 Tel Aviv, Israel
[2] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel
[3] Ben Gurion Univ Negev, Zlotowski Ctr Neurosci, IL-84105 Beer Sheva, Israel
关键词
correlated mutations; phylogenetic analysis; maximum likelihood; voltage-gated potassium channel; structural biology;
D O I
10.1016/j.jmb.2004.04.064
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A novel sequence-analysis technique for detecting correlated amino acid positions in intermediate-size protein families (50-100 sequences) was developed, and applied to study voltage-dependent gating of potassium channels. Most contemporary methods for detecting amino acid correlations within proteins use very large sets of data, typically comprising hundreds or thousands of evolutionarily related sequences, to overcome the relatively low signal-to-noise ratio in the analysis of co-variations between pairs of amino acid positions. Such methods are impractical for voltage-gated potassium (Kv) channels and for many other protein families that have not yet been sequenced to that extent. Here, we used a phylogenetic reconstruction of paralogous Kv channels to follow the evolutionary history of every pair of amino acid positions within this family, thus increasing detection accuracy of correlated amino acids relative to contemporary methods. In addition, we used a bootstrapping procedure to eliminate correlations that were statistically insignificant. These and other measures allowed us to increase the method's sensitivity, and opened the way to reliable identification of correlated positions even in intermediate-size protein families. Principal-component analysis applied to the set of correlated amino acid positions in Kv channels detected a network of inter-correlated residues, a large fraction of which were identified as gating-sensitive upon mutation. Mapping the network of correlated residues onto the 3D structure of the Kv channel from Aeropyrum pernix disclosed correlations between residues in the voltage-sensor paddle and the pore region, including regions that are involved in the gating transition. We discuss these findings with respect to the evolutionary constraints acting on the channel's various domains. The software is available on our website http://ashtoret.tau.ac.il/-sarel/CorrMut.html (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:307 / 318
页数:12
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