Data from: Structure-based network analysis of activation mechanisms in the ErbB family of receptor tyrosine kinases: the regulatory spine residues are global mediators of structural stability and allosteric interactions

The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced “superacceptor” activity in oncogenic EGFR dimers. We have found that kinase activation may be determined by allosteric interactions between modules of structurally stable residues that synchronize the dynamics in the nucleotide binding site and the αC-helix with the collective motions of the integrating αF-helix and the substrate binding site. The results of this study have pointed to a central role of the conserved His-Arg-Asp (HRD) motif in the catalytic loop and the Asp-Phe-Gly (DFG) motif as key mediators of structural stability and allosteric communications in the ErbB kinases. We have determined that residues that are indispensable for kinase regulation and catalysis often corresponded to the high centrality nodes within the protein structure network and could be distinguished by their unique network signatures. The optimal communication pathways are also controlled by these nodes and may ensure efficient allosteric signaling in the functional kinase state. Structure-based network analysis has quantified subtle effects of ATP binding on conformational dynamics and stability of the EGFR structures. Consistent with the NMR studies, we have found that nucleotide-induced modulation of the residue interaction networks is not limited to the ATP site, and may enhance allosteric cooperativity with the substrate binding region by increasing communication capabilities of mediating residues.ErbB蛋白酪氨酸激酶家族是最为关键的细胞信号转导家族之一，突变诱导的其活性调控与生物网络及人类疾病中的多种功能密切相关。本研究将ErbB激酶的分子动力学模拟（molecular dynamics simulations）与蛋白质结构网络建模（protein structure network modeling）相结合，以表征正常及致癌形式下构象平衡变化过程中残基相互作用网络的重构情况。结构稳定性分析与网络分析鉴定出以高中心性位点为核心整合形成的局部社区，这些位点对应调节脊（regulatory spine）残基。本分析为致癌表皮生长因子受体（EGFR）二聚体中突变诱导的“超受体”活性机制提供了定量视角。我们发现，激酶的激活或许由结构稳定残基模块之间的变构相互作用所决定，这些模块可将核苷酸结合位点与αC螺旋的动态变化与整合的αF螺旋及底物结合位点的集体运动同步起来。本研究结果揭示了催化环中保守的组氨酸-精氨酸-天冬氨酸（His-Arg-Asp, HRD）基序与天冬氨酸-苯丙氨酸-甘氨酸（Asp-Phe-Gly, DFG）基序作为ErbB激酶结构稳定性与变构通讯关键介导因子的核心作用。我们确定，对于激酶调节与催化不可或缺的残基，往往对应蛋白质结构网络中的高中心性节点，且可通过其独特的网络特征加以区分。最优通讯通路亦受这些节点调控，可确保功能性激酶状态下高效的变构信号传递。基于结构的网络分析量化了ATP结合对EGFR结构构象动态性与稳定性的细微影响。与核磁共振（NMR）研究结果一致，我们发现核苷酸诱导的残基相互作用网络调控并非局限于ATP结合位点，还可通过增强介导残基的通讯能力，提升与底物结合区域的变构协同性。