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Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.

ABSTRACT: Phosphoinositide 3-kinase alpha (PI3K?) 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 PI3K? activity, which can lead to oncogenesis. To assess the mechanism of the PI3K? 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 PI3K?, we observe a spontaneous detachment of the nSH2 PI3K? domain (regulatory subunit, p85?) from the helical domain (catalytic subunit, p110?) 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 p110? E545K mutation in atomic level detail and indicate a possible mechanism for the loss of regulation that E545K confers on PI3K?.

SUBMITTER: Leontiadou H

PROVIDER: S-EPMC6195558 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.

Leontiadou Hari H Galdadas Ioannis I Athanasiou Christina C Cournia Zoe Z

Scientific reports 20181019 1

Phosphoinositide 3-kinase alpha (PI3Kα) 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 constitu ...[more]

PMID: 30341384

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Project description:Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel alpha4beta2 nAChR by over 10 ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1 (Haddadian et al., J. Phys. Chem. B 2008, 112, 13981). On average there were 65 and 74 interfacial lipids around the closed- and open-channel alpha4beta2 nAChR, respectively, in the equilibrated simulation systems. In the open-channel system, 42% of the interfacial POPA had acyl chains partially inserted into intra- or intersubunit cavities, as compared to only 7% in the closed-channel alpha4beta2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller headgroup, POPA could access some nonannular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA acted not only as an acceptor for hydrogen bonding (H bonding) as POPC did, but also as a donor through its hydroxyl group for H bonding with the backbone of the protein. The charged headgroup of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the alpha4beta2. A higher number of salt bridges and hydrogen bonds (H bonds) between POPA and the alpha4beta2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR.

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Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.

Publications

Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.

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