Oncogenic mutations weaken the interactions that stabilize the p110α‐p85α heterodimer in phosphatidylinositol 3‐kinase α

Abstract

Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimeric lipid kinase that catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3). The PI3Kα signaling pathway plays an important role in cell growth, proliferation and survival. This pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110α PI3Kα subunit, is mutated. Its mutation often results in gain of enzymatic activity; however, the mechanism of activation by oncogenic mutations remains unknown. Here, using computational methods, we show that oncogenic mutations that are far from the catalytic site and increase the enzymatic affinity, destabilize the p110α/p85α dimer. By affecting the dynamics of the protein, these mutations favor the conformations that reduce the autoinhibitory effect of the p85α nSH2 domain. For example, we determined that in all the mutants, the nSH2 domain exhibits increased positional heterogeneity compared to the wild type (WT), as evidenced by changes in the fluctuation profiles computed by normal mode analysis (NMA) of coarse-grained elastic network models (ENM). Analysis of the inter-domain interactions of the WT and mutants at the p110α/p85α interface obtained using molecular dynamics (MD) simulations suggest that all the tumor-associated mutations effectively weaken the interactions between the p110α and the p85α subunits by disrupting key stabilizing interactions. These findings have important implications for understanding how oncogenic mutations change the conformational multiplicity of PI3Kα and lead to increased enzymatic activity. This mechanism may apply to other enzymes and/or macromolecular complexes that play a key role in cell signaling.

Na + coordination at the Na2 site of the Na + /I − symporter

“…This calculation was repeated 1,000 times with different random numbers, and the 1,000 values for each individual Cα atom in the chain were averaged (82). We showed that the calculation converges when more than 500 values are averaged.…”

Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85α and p85β

“…Larger truncations of C-terminal domains greatly attenuate the effects of the single cSH2 domain deletions, resulting in constructs of low activity for p85α as well as p85β. Interacting with p110, the nSH2 domain binds to the helical domain and the iSH2 domain associates with the adapter-binding and C2 domains of p110 to stabilize and inhibit the catalytic subunit [ 13 , 16 , 18 , 20 , 21 ]. Both SH2 domains play distinct roles in the regulation of PI3K activity [ 17 ].…”

Docking Study to Predict the Efficacy of Phosphatidylinositol 3-Kinase α Inhibitors

“…PIK3CA is frequently mutated in different types of cancer (Samuels and Waldman, 2010;Mangone, et al, 2012;Wang, et al, 2013;Schmidt, et al, 2018). Anomalies in p110α are associated with increased enzymatic activity of PI3K and promote oncogenesis in affected cells (Bader, et al, 2005;Echeverria, et al, 2015). Due to their roles in promoting cancer cell survival, transformation, proliferation, and migration, PI3Ks are considered promising targets in cancer therapy (Vivanco and Sawyers, 2002;Hausler, et al, 1998;Vanhaesebroeck, et al, 2010).…”