The structural basis of Akt PH domain interaction with calmodulin.
Biophys J
; 120(10): 1994-2008, 2021 05 18.
Article
em En
| MEDLINE
| ID: mdl-33775637
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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Calmodulina
/
Domínios de Homologia à Plecstrina
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Biophys J
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Turquia