43PA hotspot variants p.H1047R and p.H1047L in p110α/ΔNp63α complex affects structure, function and contributes to susceptibility metastatic breast cancer. (24th November 2019) - Linglin, Z
Abstract: Background: Hotspot constitutive activating of phosphatidylinositol 3 kinase (PI3K) signaling plays a critical role in metastatic breast cancer (MBC). Our previous studies found that oncogenic hotspot mutations of subunit alpha of PI3K (PIK3CA) within the p110α kinase domain (H1047R and H1047L) leads to cell motility and promotes tumor metastasis in invasive ductal breast carcinomas of Chinese women. This study is aimed to elucidate the mutagenetic, homology modelling and function of hotspot variants p.H1047R and p.H1047L in p110α/ΔNp63α complex. Methods: Here, an established protocol by integrated molecular dynamics, protein-protein docking with combination principal component analysis assay were employed to examine the onco-activation inhibitory function of p110α/ΔNp63α complex between wild and both p110α H1047R and p110α H1047L mutation's conformational diversity. Then, we were confirmed the possible disruption and inhibitory effect of the p110α/ΔNp63α complex at in vitromodel of MBC. Results: Partial disruption of interaction between the DNA binding domain of ΔNp63α and kinase domain of p110α were destabilized the conformation of activation loop of p110α/ΔNp63α complex in three helix regions, including H1 (resid 234-236), H2 (resid 245-249) and H3 (resid 348-355). The molecular dynamics finding clearly confirmed that ABD (resid 16-105) and C2 domain (resid 330-487) in p.H1047R mutant and RBD (resid 187-289) and kinase domain (resid 797-1068) in p.H1047L mutant are maxima difference of residue level displacements and fluctuations of p110α/ΔNp63α complex. Notably, oncogenic p.H1047L variant is more treatable and distributed structure more than p.H1047R. In vitro result show that abrogation of oncogenic hotspot mutations p.H1047R and p.H1047L in p110α/ΔNp63α complex significantly induces scattered cell growth, cell migration and invasion in MBC cell lines. Conclusions: Oncogenic hotspot mutant forms, p110αH1047R and p110αH1047L, by reducing the inhibitory effect of the ΔNp63αon the kinase domain of p110α, contributes to the progressive causatives of MBC, as well as defines a novel symbiotic strategy for understanding complex protein systems in MBC. Legal entity responsible for the study: The authors. Funding: Southwest Medical University. Disclosure: All authors have declared no conflicts of interest.