Computational Insights into the Interactions between Calmodulin and the c/nSH2 Domains of p85α Regulatory Subunit of PI3Kα: Implication for PI3Kα Activation by Calmodulin.
Computational Insights into the Interactions between Calmodulin and the c/nSH2 Domains of p85α Regulatory Subunit of PI3Kα: Implication for PI3Kα Activation by Calmodulin.
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钙调蛋白与 PI3K p85 调节亚基的 c/nSH2 结构域之间相互作用的计算见解：钙调蛋白激活 PI3K 的意义
DOI：
10.3390/ijms19010151
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发表时间：
2018-01-04
影响因子：
5.6
通讯作者：
Lu S
中科院分区：
文献类型：
--
作者：
Ni D;Liu D;Zhang J;Lu S
钙调素（CaM）和磷脂酰肌醇-3激酶（PI 3 K α）在一系列细胞内信号通路和多种肿瘤的发生发展中起着重要作用。CaM和PI 3 K α之间的串扰一直是深入研究的领域。最近的实验表明，在腺癌中，K-Ras 4 B参与CaM-PI 3 K α串扰。基于实验结果，我们最近提出了CaM和PI 3 K α与K-Ras 4 B配位形成CaM-PI 3 K α-K-Ras 4 B三元复合物，导致胰腺导管腺癌形成的假说。然而，CaM-PI 3 K α串扰的机制尚未解决。本研究基于分子模拟和分子动力学模拟，探讨了钙调素与磷脂酰肌醇3激酶α p85α亚基c/nSH 2结构域的相互作用。我们证明了CaM可以与c/nSH 2结构域相互作用，并揭示了相互作用的细节。此外，我们还发现了CaM-cSH 2和CaM-nSH 2相互作用的可能模式，并利用它们构建了一个完整的CaM-PI 3 K α复合物模型。CaM-PI 3 K α相互作用的结构模型不仅支持了我们先前的三元复合物假说，而且对于针对CaM-PI 3 K α蛋白质-蛋白质相互作用的药物设计也是有用的。
Calmodulin (CaM) and phosphatidylinositide-3 kinase (PI3Kα) are well known for their multiple roles in a series of intracellular signaling pathways and in the progression of several human cancers. Crosstalk between CaM and PI3Kα has been an area of intensive research. Recent experiments have shown that in adenocarcinoma, K-Ras4B is involved in the CaM-PI3Kα crosstalk. Based on experimental results, we have recently put forward a hypothesis that the coordination of CaM and PI3Kα with K-Ras4B forms a CaM-PI3Kα-K-Ras4B ternary complex, which leads to the formation of pancreatic ductal adenocarcinoma. However, the mechanism for the CaM-PI3Kα crosstalk is unresolved. Based on molecular modeling and molecular dynamics simulations, here we explored the potential interactions between CaM and the c/nSH2 domains of p85α subunit of PI3Kα. We demonstrated that CaM can interact with the c/nSH2 domains and the interaction details were unraveled. Moreover, the possible modes for the CaM-cSH2 and CaM-nSH2 interactions were uncovered and we used them to construct a complete CaM-PI3Kα complex model. The structural model of CaM-PI3Kα interaction not only offers a support for our previous ternary complex hypothesis, but also is useful for drug design targeted at CaM-PI3Kα protein-protein interactions.
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影响因子：
37.3
作者：
Abubaker J;Bavi P;Al-Haqawi W;Jehan Z;Munkarah A;Uddin S;Al-Kuraya KS
通讯作者：
Al-Kuraya KS
影响因子：
14.9
作者：
Baspinar A;Cukuroglu E;Nussinov R;Keskin O;Gursoy A
通讯作者：
Gursoy A
影响因子：
5.6
作者：
BABU, YS;BUGG, CE;COOK, WJ
通讯作者：
COOK, WJ
影响因子：
4.8
作者：
Jang, Hyunbum;Banerjee, Avik;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
DOI：
10.1007/978-1-59745-398-1_30
发表时间：
2008-01-01
期刊：
FUNCTIONAL PROTEOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Keskin, Ozlem;Nussinov, Ruth;Gursoy, Attila
通讯作者：
Gursoy, Attila