Computational Insights into the Interactions between Calmodulin and the c/nSH2 Domains of p85 Regulatory Subunit of PI3K: Implication for PI3K Activation by Calmodulin

Calmodulin (CaM) and phosphatidylinositide-3 kinase (PI3K) are well known for their multiple roles in a series of intracellular signaling pathways and in the progression of several human cancers. Crosstalk between CaM and PI3K has been an area of intensive research. Recent experiments have shown that in adenocarcinoma, K-Ras4B is involved in the CaM-PI3K crosstalk. Based on experimental results, we have recently put forward a hypothesis that the coordination of CaM and PI3K with K-Ras4B forms a CaM-PI3K-K-Ras4B ternary complex, which leads to the formation of pancreatic ductal adenocarcinoma. However, the mechanism for the CaM-PI3K crosstalk is unresolved. Based on molecular modeling and molecular dynamics simulations, here we explored the potential interactions between CaM and the c/nSH2 domains of p85 subunit of PI3K. We demonstrated that CaM can interact with the c/nSH2 domains and the interaction details were unraveled. Moreover, the possible modes for the CaM-cSH2 and CaM-nSH2 interactions were uncovered and we used them to construct a complete CaM-PI3K complex model. The structural model of CaM-PI3K interaction not only offers a support for our previous ternary complex hypothesis, but also is useful for drug design targeted at CaM-PI3K protein-protein interactions.