Project Acronym: PI3Ka-E545KTitle: Selective inhibition of the PI3Kα E545K mutant through MD simulations, in vitro assays and SPR experimentsAffiliation: biomedical research foundation, academy of athensPi: Zoe CourniaResearch Field: biochemistry, bioinformatics and life sciences
Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.
by Leontiadou, H., Galdadas, I., Athanasiou, C. and Cournia, Z.
Abstract:
Phosphoinositide 3-kinase alpha (PI3Kalpha) is involved in fundamental cellular processes including cell proliferation and differentiation and is frequently mutated in human malignancies. One of the most common mutations is E545K, which results in an amino acid substitution of opposite charge. It has been recently proposed that in this oncogenic charge-reversal mutation, the interactions between the protein catalytic and regulatory subunits are abrogated, resulting in loss of regulation and constitutive PI3Kalpha activity, which can lead to oncogenesis. To assess the mechanism of the PI3Kalpha E545K activating mutation, extensive Molecular Dynamics simulations were performed to examine conformational changes differing between the wild type (WT) and mutant proteins as they occur in microsecond simulations. In the E545K mutant PI3Kalpha, we observe a spontaneous detachment of the nSH2 PI3Kalpha domain (regulatory subunit, p85alpha) from the helical domain (catalytic subunit, p110alpha) causing significant loss of communication between the regulatory and catalytic subunits. We examine the allosteric network of the two proteins and show that a cluster of residues around the mutation is important for delivering communication signals between the catalytic and regulatory subunits. Our results demonstrate the dynamical and structural effects induced by the p110alpha E545K mutation in atomic level detail and indicate a possible mechanism for the loss of regulation that E545K confers on PI3Kalpha.
Reference:
Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations. (Leontiadou, H., Galdadas, I., Athanasiou, C. and Cournia, Z.), In Sci Rep, volume 8, 2018.
Bibtex Entry:
@article{pmid30341384, author = {Leontiadou, H. and Galdadas, I. and Athanasiou, C. and Cournia, Z. }, title = {Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.}, journal = {Sci Rep}, year = {2018}, bibyear = {2018}, volume = {8}, number = {1}, pages = {15544}, month = {Oct}, doi = {10.1038/s41598-018-27044-6}, url = {https://doi.org/10.1038/s41598-018-27044-6}, abstract = {Phosphoinositide 3-kinase alpha (PI3Kalpha) is involved in fundamental cellular processes including cell proliferation and differentiation and is frequently mutated in human malignancies. One of the most common mutations is E545K, which results in an amino acid substitution of opposite charge. It has been recently proposed that in this oncogenic charge-reversal mutation, the interactions between the protein catalytic and regulatory subunits are abrogated, resulting in loss of regulation and constitutive PI3Kalpha activity, which can lead to oncogenesis. To assess the mechanism of the PI3Kalpha E545K activating mutation, extensive Molecular Dynamics simulations were performed to examine conformational changes differing between the wild type (WT) and mutant proteins as they occur in microsecond simulations. In the E545K mutant PI3Kalpha, we observe a spontaneous detachment of the nSH2 PI3Kalpha domain (regulatory subunit, p85alpha) from the helical domain (catalytic subunit, p110alpha) causing significant loss of communication between the regulatory and catalytic subunits. We examine the allosteric network of the two proteins and show that a cluster of residues around the mutation is important for delivering communication signals between the catalytic and regulatory subunits. Our results demonstrate the dynamical and structural effects induced by the p110alpha E545K mutation in atomic level detail and indicate a possible mechanism for the loss of regulation that E545K confers on PI3Kalpha.}, }