Correlated mutation analysis on the catalytic domains of serine/threonine protein kinases.
Correlated mutation analysis on the catalytic domains of serine/threonine protein kinases.
复制标题
丝氨酸/苏氨酸蛋白激酶催化结构域的相关突变分析
DOI：
10.1371/journal.pone.0005913
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发表时间：
2009-06-15
期刊：
影响因子：
3.7
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Xu F;Du P;Shen H;Hu H;Wu Q;Xie J;Yu L
背景蛋白激酶（PKs）是真核细胞中最大的信号蛋白家族，参与细胞调控的各个方面。虽然对PKs磷酸化底物的机制的研究取得了很大进展，但PKs通过其结构保守的催化结构域来保证底物特异性的具体机制仍不清楚。基于大量不同序列数据的相关突变分析可能会为这个问题提供新的见解。方法/主要发现统计耦合，残基相关性和互信息分析沿着聚类分析的Ser/Thr PK家族的催化结构域的结构为基础的多序列比对。两个集群的高度耦合的网站进行了鉴定。将这些位置映射到PK催化结构域的3D结构上，表明这两组位置形成了两个物理上紧密的网络。我们将这两个网络分别命名为θ形网络和γ形网络。结论/意义θ型网络连接活性位点裂隙和底物结合区，可能参与PKs与底物的识别和相互作用。γ形网络主要位于底物结合区的一侧，连接活化环和底物结合区。它可能在催化前支持活化环和底物结合区，并参与磷酰基转移后的产物释放。我们的研究结果与实验观测结果具有显着的相关性，并可以作为指导进一步的实验和理论研究的PKs与其底物的相互作用机制。
Background Protein kinases (PKs) have emerged as the largest family of signaling proteins in eukaryotic cells and are involved in every aspect of cellular regulation. Great progresses have been made in understanding the mechanisms of PKs phosphorylating their substrates, but the detailed mechanisms, by which PKs ensure their substrate specificity with their structurally conserved catalytic domains, still have not been adequately understood. Correlated mutation analysis based on large sets of diverse sequence data may provide new insights into this question. Methodology/Principal Findings Statistical coupling, residue correlation and mutual information analyses along with clustering were applied to analyze the structure-based multiple sequence alignment of the catalytic domains of the Ser/Thr PK family. Two clusters of highly coupled sites were identified. Mapping these positions onto the 3D structure of PK catalytic domain showed that these two groups of positions form two physically close networks. We named these two networks as θ-shaped and γ-shaped networks, respectively. Conclusions/Significance The θ-shaped network links the active site cleft and the substrate binding regions, and might participate in PKs recognizing and interacting with their substrates. The γ-shaped network is mainly situated in one side of substrate binding regions, linking the activation loop and the substrate binding regions. It might play a role in supporting the activation loop and substrate binding regions before catalysis, and participate in product releasing after phosphoryl transfer. Our results exhibit significant correlations with experimental observations, and can be used as a guide to further experimental and theoretical studies on the mechanisms of PKs interacting with their substrates.
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