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@article{991215,
author = {Ionescu, CrinaandMaria and Svobodová Vařeková, Radka and Prehn, Jochen HM and Huber, Heinrich J and Koča, Jaroslav},
article_location = {San Francisco},
article_number = {6},
doi = {http://dx.doi.org/10.1371/journal.pcbi.1002565},
keywords = {apoptosis; Bax; Bak; atomic charge; allostery},
language = {eng},
issn = {1553-7358},
journal = {PLoS Computational Biology},
title = {Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation},
url = {http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002565},
volume = {8},
year = {2012}
}
TY - JOUR
ID - 991215
AU - Ionescu, Crina-Maria - Svobodová Vařeková, Radka - Prehn, Jochen HM - Huber, Heinrich J - Koča, Jaroslav
PY - 2012
TI - Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation
JF - PLoS Computational Biology
VL - 8
IS - 6
SP - "nestránkováno"
EP - "nestránkováno"
PB - PUBLIC LIBRARY SCIENCE
SN - 15537358
KW - apoptosis
KW - Bax
KW - Bak
KW - atomic charge
KW - allostery
UR - http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002565
L2 - http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002565
N2 - The pro-apoptotic proteins Bax and Bak are essential for executing programmed cell death (apoptosis), yet the mechanism of their activation is not properly understood at the structural level. For the first time in cell death research, we calculated intra-protein charge transfer in order to study the structural alterations and their functional consequences during Bax activation. Using an electronegativity equalization model, we investigated the changes in the Bax charge profile upon activation by a functional peptide of its natural activator protein, Bim. We found that charge reorganizations upon activator binding mediate the exposure of the functional sites of Bax, rendering Bax active. The affinity of the Bax C-domain for its binding groove is decreased due to the Arg94-mediated abrogation of the Ser184-Asp98 interaction. We further identified a network of charge reorganizations that confirms previous speculations of allosteric sensing, whereby the activation information is conveyed from the activation site, through the hydrophobic core of Bax, to the well-distanced functional sites of Bax. The network was mediated by a hub of three residues on helix 5 of the hydrophobic core of Bax. Sequence and structural alignment revealed that this hub was conserved in the Bak amino acid sequence, and in the 3D structure of folded Bak. Our results suggest that allostery mediated by charge transfer is responsible for the activation of both Bax and Bak, and that this might be a prototypical mechanism for a fast activation of proteins during signal transduction. Our method can be applied to any protein or protein complex in order to map the progress of allosteric changes through the proteins' structure.
ER -
IONESCU, Crina-Maria, Radka SVOBODOVÁ VAŘEKOVÁ, Jochen HM PREHN, Heinrich J HUBER and Jaroslav KOČA. Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation. \textit{PLoS Computational Biology}. San Francisco: PUBLIC LIBRARY SCIENCE, 2012, vol.~8, No~6, p.~''nestránkováno'', 11 pp. ISSN~1553-7358. Available from: https://dx.doi.org/10.1371/journal.pcbi.1002565.
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