Weako Jackson, Jang Hyunbum, Keskin Ozlem, Nussinov Ruth, Gursoy Attila
Computational Science and Engineering Program, Koç University, Istanbul, Turkey.
Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland.
Biophys J. 2021 May 18;120(10):1994-2008. doi: 10.1016/j.bpj.2021.03.018. Epub 2021 Mar 26.
Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a β-strand rather than an α-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP, the polar head of PIP, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3Kα activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.
Akt在Ras/PI3K/Akt/mTOR信号通路中起关键作用。在乳腺癌中，Akt通过其普列克底物蛋白同源结构域（PHD）与钙调蛋白（CaM）的相互作用而转位至质膜。在膜上，磷脂酰肌醇-3,4,5-三磷酸（PIP）促进的构象变化释放CaM，并促进苏氨酸308和丝氨酸473的磷酸化及激活。在此，我们利用建模和分子动力学模拟，旨在弄清楚CaM在原子水平上如何与Akt的PHD相互作用。我们的模拟表明，CaM-PHD相互作用在热力学上是稳定的，且涉及一条β链而非α螺旋，这与核磁共振数据一致，并且静电和疏水相互作用至关重要。PHD与CaM叶相互作用；然而，存在多种可能的模式。PIP的极性头部肌醇-1,4,5-三磷酸（IP）会削弱CaM-PHD相互作用，这暗示了质膜上的释放机制。最近，我们在原子水平上揭示了PI3Kα激活的机制以及Ras在激活中作用的结构基础。在此，我们的原子结构数据阐明了CaM在质膜上如何与Akt相互作用、传递并释放Akt（Ras/PI3K途径中的下一个节点）的机制。
