Allosteric communication across the native and mutated KIT receptor tyrosine kinase.
Allosteric communication across the native and mutated KIT receptor tyrosine kinase.
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DOI：
10.1371/journal.pcbi.1002661
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发表时间：
2012
影响因子：
4.3
通讯作者：
Tchertanov L
中科院分区：
文献类型：
--
作者：
Laine E;Auclair C;Tchertanov L
细胞信号传导的一个基本目标是理解变构通讯，即起源于蛋白质一个位点的信号依赖性地传播到影响远端功能位点的过程。在这里，我们描述了受体酪氨酸激酶KIT的变构调节。我们的分析证明，在激活环（A-环）和天然蛋白质中的远端质膜区域（JMR）之间建立的通信途径被位于A-环中的致癌突变D816 V破坏。计算机模拟诱变提供了一种通过引入平衡第二突变D 792 E恢复天然KIT中检测到的蛋白质通讯的合理方法。在天然和突变的KIT中观察到的通信模式与这些蛋白质的结构和动力学特征完全相关。特别地，在致癌突变体中表现为JMR的重要结构重组的D816 V突变的远距离效应在双突变体D816 V/D 792 E中完全消失。通过使用由通信途径和独立的动态片段组成的模块化网络表示来进行在不同形式的KIT（天然和突变体）中的变构通信的详细表征。这样的表示允许丰富一个纯粹的机械相互作用为基础的模型，蛋白质通信通过引入协调一致的本地原子波动。该方法在KIT受体上得到验证，可指导其他受体酪氨酸激酶的生理病理活性的合理调节。大多数功能重要的生物过程是由个别蛋白质内和跨蛋白质复合物的变构通讯调节的。受体酪氨酸激酶（RTK）控制信号转导途径，因此代表了一个典型的范例。突变引起的RTK活性失调损害了重要的细胞生理功能，并导致严重的人类疾病。本研究的重点是跨三维结构的RTK KIT胞质区域的变构通信。结合信息传输的机制模型与协调的局部原子波动的分析，我们研究并比较了天然和D816 V突变蛋白质中的通信概况。这种方法允许本地化和可视化的通信路线在天然KIT和揭示，这些路线被破坏的突变体D816 V。我们提出计算机诱变作为恢复天然KIT中检测到的通信的手段。我们的工作揭示了RTK中的变构通信，这是一种在信号传导途径中发挥重要作用的现象，尽管实验没有提供从一个结构元件到另一个结构元件所遵循的路径的原子细节。对疾病相关激酶突变影响的分子决定因素的合理理解可能有助于靶向治疗的改进。
A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originated at one site in a protein propagate dependably to affect remote functional sites. Here, we describe the allosteric regulation of the receptor tyrosine kinase KIT. Our analysis evidenced that communication routes established between the activation loop (A-loop) and the distant juxtamembrane region (JMR) in the native protein were disrupted by the oncogenic mutation D816V positioned in the A-loop. In silico mutagenesis provided a plausible way of restoring the protein communication detected in the native KIT by introducing a counter-balancing second mutation D792E. The communication patterns observed in the native and mutated KIT correlate perfectly with the structural and dynamical features of these proteins. Particularly, a long-distance effect of the D816V mutation manifested as an important structural re-organization of the JMR in the oncogenic mutant was completely vanished in the double mutant D816V/D792E. This detailed characterization of the allosteric communication in the different forms of KIT, native and mutants, was performed by using a modular network representation composed of communication pathways and independent dynamic segments. Such representation permits to enrich a purely mechanistic interaction-based model of protein communication by the introduction of concerted local atomic fluctuations. This method, validated on KIT receptor, may guide a rational modulation of the physiopathological activities of other receptor tyrosine kinases. The majority of functionally important biological processes are regulated by allosteric communication within individual proteins and across protein complexes. Receptor tyrosine kinases (RTKs) control signal transduction pathways and consequently represent a typical paradigm. The mutation-induced deregulation of RTK activity impairs crucial cellular physiological functions and causes serious human diseases. The present study focuses on the allosteric communication across the three-dimensional structure of the RTK KIT cytoplasmic region. Combining a mechanistic model of information transmission with the analysis of concerted local atomic fluctuations we examined and compared the communication profiles in the native and D816V-mutated proteins. This approach permitted to localize and visualize communication routes in the native KIT and revealed that these routes were disrupted in the mutant D816V. We proposed in silico mutagenesis as a mean to restore the communication detected in the native KIT. Our work sheds light on the allosteric communication in RTKs, a phenomenon playing an essential role in signaling pathways albeit experiments do not provide the atomic details of the path followed in going from one structural element to the other. A rational understanding of the molecular determinants underlying the effects of disease-related kinase mutations may contribute to the improvement of targeted therapies.
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DOI：
10.1016/j.str.2009.06.008
发表时间：
2009-08-12
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
del Sol A;Tsai CJ;Ma B;Nussinov R
通讯作者：
Nussinov R
影响因子：
2.9
作者：
Banavali, Nilesh K.;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
2.9
作者：
Banavali, Nilesh K.;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
9.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.