Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.

The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA...

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Autores principales:	Paraskevi Gkeka, Thomas Evangelidis, Maria Pavlaki, Vasiliki Lazani, Savvas Christoforidis, Bogos Agianian, Zoe Cournia
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7352bbfc2f534516aba019fb098af934
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spelling	oai:doaj.org-article:7352bbfc2f534516aba019fb098af9342021-11-25T05:40:40ZInvestigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.1553-734X1553-735810.1371/journal.pcbi.1003895https://doaj.org/article/7352bbfc2f534516aba019fb098af9342014-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1003895https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation.Paraskevi GkekaThomas EvangelidisMaria PavlakiVasiliki LazaniSavvas ChristoforidisBogos AgianianZoe CourniaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 10, p e1003895 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Paraskevi Gkeka Thomas Evangelidis Maria Pavlaki Vasiliki Lazani Savvas Christoforidis Bogos Agianian Zoe Cournia Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
description	The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation.
format	article
author	Paraskevi Gkeka Thomas Evangelidis Maria Pavlaki Vasiliki Lazani Savvas Christoforidis Bogos Agianian Zoe Cournia
author_facet	Paraskevi Gkeka Thomas Evangelidis Maria Pavlaki Vasiliki Lazani Savvas Christoforidis Bogos Agianian Zoe Cournia
author_sort	Paraskevi Gkeka
title	Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
title_short	Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
title_full	Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
title_fullStr	Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
title_full_unstemmed	Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
title_sort	investigating the structure and dynamics of the pik3ca wild-type and h1047r oncogenic mutant.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7352bbfc2f534516aba019fb098af934
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Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.

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