Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases.
Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases.
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DOI：
10.1371/journal.pcbi.1002179
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Verkhivker GM
中科院分区：
文献类型：
--
作者：
Dixit A;Verkhivker GM
关于变构激酶复合物的新结构信息和不断增长的变构抑制剂需要一种系统策略来描述和分类变构调节和控制激酶活性的远程通讯机制。在这项工作中，我们根据调节复合物的多尺度模拟和蛋白质信号传播的计算模型的结果，研究了 ABL 和 EGFR 激酶中远程通信的机制。这些方法已被系统地应用于阐明 ABL 和 EGFR 多域调节复合物中变构信号的组织分子原理，并分析看门人癌症突变的变构特征。我们提出的证据表明，变构激活机制可能在 ABL 和 EGFR 调节复合物中普遍进化，作为组织 αF 螺旋与构象适应性 αI 螺旋和 αC 螺旋之间功能串扰的产物。这些结构元素形成了有效通信的簇的动态网络，可以控制远程域间耦合和变构激活。这项研究的结果揭示了看门人癌症突变作为激酶激活催化剂的统一效应，导致变构耦合片段之间的远程通讯增强以及活性激酶形式的稳定。这项研究的结果可以协调最近关于变构抑制和蛋白激酶结合位点之间的远程协同性的实验研究。本研究为变构激酶信号传导的机制方面提供了新颖的分子见解，并在原子水平上提供了蛋白激酶激活机制的定量图景。尽管最近在蛋白激酶动态调节的计算和实验研究方面取得了进展，但对长程通讯和突变诱导信号控制激酶活性机制的机械理解在很大程度上仍然是定性的。在这项研究中，我们对 ABL 和 EGFR 激酶的变构激活进行了系统建模和分析，复杂程度不断增加 - 从催化结构域到多结构域调节复合物。这项研究的结果揭示了蛋白激酶变构信号的组织结构和机制原理。尽管 ABL 和 EGFR 激酶的激活机制是通过获得结构上不同的调节复合物而进化的，但我们发现常见功能片段（αF-螺旋和 αC-螺旋）之间的长程域间通信可能对变构激活很重要。研究结果揭示了激活癌症突变的分子特征，并揭示了蛋白激酶中突变诱导信号传导的一般机制。对激酶突变分子特征的深入理解和进一步表征可能有助于更好地合理化突变对临床结果的影响，并促进基于分子的治疗策略来对抗激酶突变依赖性肿瘤发生。
The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic aspects of long-range communications in ABL and EGFR kinases based on the results of multiscale simulations of regulatory complexes and computational modeling of signal propagation in proteins. These approaches have been systematically employed to elucidate organizing molecular principles of allosteric signaling in the ABL and EGFR multi-domain regulatory complexes and analyze allosteric signatures of the gate-keeper cancer mutations. We have presented evidence that mechanisms of allosteric activation may have universally evolved in the ABL and EGFR regulatory complexes as a product of a functional cross-talk between the organizing αF-helix and conformationally adaptive αI-helix and αC-helix. These structural elements form a dynamic network of efficiently communicated clusters that may control the long-range interdomain coupling and allosteric activation. The results of this study have unveiled a unifying effect of the gate-keeper cancer mutations as catalysts of kinase activation, leading to the enhanced long-range communication among allosterically coupled segments and stabilization of the active kinase form. The results of this study can reconcile recent experimental studies of allosteric inhibition and long-range cooperativity between binding sites in protein kinases. The presented study offers a novel molecular insight into mechanistic aspects of allosteric kinase signaling and provides a quantitative picture of activation mechanisms in protein kinases at the atomic level. Despite recent progress in computational and experimental studies of dynamic regulation in protein kinases, a mechanistic understanding of long-range communication and mechanisms of mutation-induced signaling controlling kinase activity remains largely qualitative. In this study, we have performed a systematic modeling and analysis of allosteric activation in ABL and EGFR kinases at the increasing level of complexity - from catalytic domain to multi-domain regulatory complexes. The results of this study have revealed organizing structural and mechanistic principles of allosteric signaling in protein kinases. Although activation mechanisms in ABL and EGFR kinases have evolved through acquisition of structurally different regulatory complexes, we have found that long-range interdomain communication between common functional segments (αF-helix and αC-helix) may be important for allosteric activation. The results of study have revealed molecular signatures of activating cancer mutations and have shed the light on general mechanistic aspects of mutation-induced signaling in protein kinases. An advanced understanding and further characterization of molecular signatures of kinase mutations may aid in a better rationalization of mutational effects on clinical outcomes and facilitate molecular-based therapeutic strategies to combat kinase mutation-dependent tumorigenesis.
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