Oncogenic mutations weaken the interactions that stabilize the p110α‐p85α heterodimer in phosphatidylinositol 3‐kinase α. (24th July 2015)

• Record Type: Journal Article
• Authors: Echeverria, Ignacia; Liu, Yunlong; Gabelli, Sandra B.; Amzel, L. Mario
• Is Part Of: FEBS journal. Volume 282:Number 18(2015)
• Page Start: 3528
• Page End: 3542
• Publication Date: 2015-07-24
• Subjects: allostery -- molecular dynamics simulations -- normal mode analysis -- oncogenic mutations -- phosphatidylinositol 3‐kinase activation; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13365
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Phosphatidylinositol 3‐kinase (PI3K) α is a heterodimeric lipid kinase that catalyzes the conversion of phosphoinositol‐4, 5‐bisphosphate to phosphoinositol‐3, 4, 5‐trisphosphate. 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 of the mutants, the nSH2 domain shows increased positional heterogeneity as compared with the wild‐type, as demonstrated by changes in the fluctuation profiles computed by normal mode analysis of coarse‐grained elastic network models. Analysis of the interdomain interactions of the wild‐type and mutants at the p110α–p85α interface obtained with molecular dynamics simulations suggest that all of the tumor‐associated mutations effectively weaken the interactions between p110α and p85α 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. Abstract : PI3Kα oncogenic mutations are often located at the interface between different domains. Using computational methods we studied oncogenic mutations located at the helical‐nSH2, C2‐iSH2 and ABD‐kinase domain interfaces. These mutations have the effect of weakening the interactions that stabilize the p110α/p85α heterodimer, leading to reversal of the autoinhibition by the nSH2 domain observed for the wild type.