The Structural Basis of Akt PH Domain Interaction with Calmodulin

Author:

Weako,Jackson

Jang, Hyunbum

Keskin, Ozlem

Nussinov,Ruth

Gursoy, Attila
Author Address

Computational Science and Engineering Program, Ko 231; University, Istanbul 34450, Turkey., Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, U.S.A., Department of Chemical and Biological Engineering, Ko 231; University, Istanbul 34450, Turkey., Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, U.S.A.; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: nussinor@mail.nih.gov., Department of Computer Engineering, Ko 231; University, Istanbul 34450, Turkey. Electronic address: agursoy@ku.edu.tr.,

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 modelling and molecular dynamics (MD) simulations we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that the CaM-PHD interaction is thermodynamically stable and involves a ß-strand, rather than an a-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. 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 PI3Ka 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. Copyright © 2021 Biophysical Society. All rights reserved.

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