Phosphorylated Calmodulin Promotes PI3K Activation by Binding its SH2 Domains
Friday, September 15, 2017 — Poster Session IV
- Min Zhang
- Hyu Jang
- Rut Nussinov
How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. Data indicated that CaM binds to and stimulates PI3Ka/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr99 (pY99) enhances PI3Ka activation. PI3Ka is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Ka has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent molecular dynamics simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations and uncover PI3Ka’s mechanism of activation. pCaMs form strong and stable interactions with both nSH2 and cSH2 domains, with pY99 being the dominant contributor. Unexpectedly, despite the high similarity between the two SH2 domains, we observe that nSH2 prefers an extended CaM conformation, whereas cSH2 prefers a collapsed conformation. Notably, collapsed CaM is observed following binding of an extended CaM to K-Ras4B. Thus, the more populated extended pCaM conformation targets nSH2 to release its autoinhibition of p110 catalytic sites. This executes the key activation step of PI3Ka. Independently, K-Ras4B allosterically activates p110. These events are at the cell membrane, which contributes to tighten the PI3Ka Ras binding domain (RBD)/K-Ras4B interaction, to accomplish K-Ras4B allosteric activation, with a minor contribution from cSH2.
Category: Computational Biology