Conformational frustration in calmodulin-target recognition.
Conformational frustration in calmodulin-target recognition.
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DOI：
10.1002/jmr.2413
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发表时间：
2015-02
影响因子：
2.7
通讯作者：
Cheung, Margaret S.
中科院分区：
文献类型：
--
作者：
Tripathi, Swarnendu;Wang, Qian;Zhang, Pengzhi;Hoffman, Laurel;Waxham, M. Neal;Cheung, Margaret S.
关键词：
钙调素（CaM）是一种主要的钙（Ca 2+）信号蛋白，特异性识别和激活高度多样化的靶蛋白。我们探索了目标识别的分子基础的钙调素与肽代表的钙调素结合结构域从两个钙离子-钙调素依赖性激酶，CaMKI和CaMKII，通过采用实验约束的分子模拟。详细的结合途径分析表明，两个CaM靶肽，虽然在长度和净电荷相似，遵循不同的路线，导致更高的结合挫折在CaM-CaMKII复合物比CaM-CaMKI复合物。我们发现，结合挫折的分子起源是由与CaM的C-结构域形成的分子间接触引起的，所述分子间接触需要在与CaM的N-结构域形成分子间接触之前被破坏。我们认为，结合挫折是重要的，用于确定涉及大的结构波动的蛋白质的识别过程的动力学。
Calmodulin (CaM) is a primary calcium (Ca2+) signaling protein that specifically recognizes and activates highly diverse target proteins. We explored the molecular basis of target recognition of CaM with peptides representing the CaM-binding domains from two Ca2+-CaM dependent kinases, CaMKI and CaMKII, by employing experimentally-constrained molecular simulations. Detailed binding route analysis revealed that the two CaM target peptides, although similar in length and net charge, follow distinct routes that lead to a higher binding frustration in the CaM-CaMKII complex than the CaM-CaMKI complex. We discovered that the molecular origin of the binding frustration is caused by intermolecular contacts formed with the C-domain of CaM that need to be broken before the formation of intermolecular contacts with the N-domain of CaM. We argue that the binding frustration is important for determining the kinetics of the recognition process of proteins involving large structural fluctuations.
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