The structural basis of Akt PH domain interaction with calmodulin. Weako, J., Jang, H., Keskin, O., Nussinov, R., & Gursoy, A. Biophysical Journal, 2021. ![The structural basis of Akt PH domain interaction with calmodulin [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 3 downloads 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 PIP3 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. IP4, the polar head of PIP3, 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.
@article{WEAKO2021,
author = "Weako, Jackson and Jang, Hyunbum and Keskin, Ozlem and Nussinov, Ruth and Gursoy, Attila",
title = "The structural basis of Akt PH domain interaction with calmodulin",
journal = "Biophysical Journal",
year = "2021",
issn = "0006-3495",
doi = "https://doi.org/10.1016/j.bpj.2021.03.018",
url = "https://www.sciencedirect.com/science/article/pii/S0006349521002484",
abstract = "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 PIP3 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. IP4, the polar head of PIP3, 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.",
keywords = "CBM"
}
Downloads: 3
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