Charge Profile Analysis Reveals That Activation of
Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer
Mediated Allosteric Regulation

J 2012

Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation

IONESCU, Crina-Maria, Radka SVOBODOVÁ VAŘEKOVÁ, Jochen HM PREHN, Heinrich J HUBER, Jaroslav KOČA et. al.

Basic information

Original name

Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation

Authors

IONESCU, Crina-Maria (642 Romania, belonging to the institution), Radka SVOBODOVÁ VAŘEKOVÁ (203 Czech Republic, belonging to the institution), Jochen HM PREHN (276 Germany), Heinrich J HUBER (40 Austria) and Jaroslav KOČA (203 Czech Republic, guarantor, belonging to the institution)

Edition

PLoS Computational Biology, San Francisco, PUBLIC LIBRARY SCIENCE, 2012, 1553-7358

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10600 1.6 Biological sciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.867

RIV identification code

RIV/00216224:14740/12:00057573

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1371/journal.pcbi.1002565

UT WoS

000305965300033

Keywords in English

apoptosis; Bax; Bak; atomic charge; allostery

Abstract

V originále

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.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

GD301/09/H004, research and development project

Name: Molekulární a strukturní biologie vybraných cytostatik. Od mechanistických studií k chemoterapii rakoviny

Investor: Czech Science Foundation

286154, interní kód MU

Name: SYLICA - Synergies of Life and Material Sciences to Create a New Future (Acronym: SYLICA)

Investor: European Union, Capacities

Citovat

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. 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.

@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.

Detailed Information on Publication Record