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Charge profile analysis reveals that activation of pro-apoptotic regulators Bax and Bak relies on charge transfer mediated allosteric regulation.

Ionescu CM, Svobodová Vařeková R, Prehn JH, Huber HJ, Koča J - PLoS Comput. Biol. (2012)

Bottom Line: The affinity of the Bax C-domain for its binding groove is decreased due to the Arg94-mediated abrogation of the Ser184-Asp98 interaction.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.

View Article: PubMed Central - PubMed

Affiliation: CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

ABSTRACT
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.

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Related in: MedlinePlus

Validation of EEM models by comparing EEM atomic charges against QM atomic charges.Statistical descriptors comprising the average correlation coefficient (Ravg), the average root mean square deviation (RMSDavg) and the average absolute difference (Davg) are given. These descriptors quantify the agreement between EEM model charges and QM charges for molecules belonging to the reference sets RS1 and RS2, and for five further test molecules T1–T5. All quantities are given in elementary charges (1 e∼1.602×10−19 coulombs). The names of the parameter sets encode the reference set and atom classification scheme based on which they were developed (RS1-E, RS1-EX, RS2-E, RS2-EX). Good agreement between QM and EEM charges was found for all data sets, as Ravg is close to 1, and RMSDavg and Davg are minimal. Calibrations that used the coarse atom type classification ‘E’ gave a similarly good agreement as those where the more detailed classification scheme ‘EX’ was used.
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pcbi-1002565-g003: Validation of EEM models by comparing EEM atomic charges against QM atomic charges.Statistical descriptors comprising the average correlation coefficient (Ravg), the average root mean square deviation (RMSDavg) and the average absolute difference (Davg) are given. These descriptors quantify the agreement between EEM model charges and QM charges for molecules belonging to the reference sets RS1 and RS2, and for five further test molecules T1–T5. All quantities are given in elementary charges (1 e∼1.602×10−19 coulombs). The names of the parameter sets encode the reference set and atom classification scheme based on which they were developed (RS1-E, RS1-EX, RS2-E, RS2-EX). Good agreement between QM and EEM charges was found for all data sets, as Ravg is close to 1, and RMSDavg and Davg are minimal. Calibrations that used the coarse atom type classification ‘E’ gave a similarly good agreement as those where the more detailed classification scheme ‘EX’ was used.

Mentions: Overall, the results in Figure 3 suggested that the finer grained atom classification scheme ‘EX’ only modestly improved the accuracy compared to the scheme ‘E’ based on chemical elements alone. The good agreement between QM and EEM charges for all data sets suggested that both atom classification schemes can provide satisfactory calibration results. Moreover, our model was able to compute EEM atomic charges in less than 1 second for any of the reference or test molecules using our previously published implementation [39].


Charge profile analysis reveals that activation of pro-apoptotic regulators Bax and Bak relies on charge transfer mediated allosteric regulation.

Ionescu CM, Svobodová Vařeková R, Prehn JH, Huber HJ, Koča J - PLoS Comput. Biol. (2012)

Validation of EEM models by comparing EEM atomic charges against QM atomic charges.Statistical descriptors comprising the average correlation coefficient (Ravg), the average root mean square deviation (RMSDavg) and the average absolute difference (Davg) are given. These descriptors quantify the agreement between EEM model charges and QM charges for molecules belonging to the reference sets RS1 and RS2, and for five further test molecules T1–T5. All quantities are given in elementary charges (1 e∼1.602×10−19 coulombs). The names of the parameter sets encode the reference set and atom classification scheme based on which they were developed (RS1-E, RS1-EX, RS2-E, RS2-EX). Good agreement between QM and EEM charges was found for all data sets, as Ravg is close to 1, and RMSDavg and Davg are minimal. Calibrations that used the coarse atom type classification ‘E’ gave a similarly good agreement as those where the more detailed classification scheme ‘EX’ was used.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375244&req=5

pcbi-1002565-g003: Validation of EEM models by comparing EEM atomic charges against QM atomic charges.Statistical descriptors comprising the average correlation coefficient (Ravg), the average root mean square deviation (RMSDavg) and the average absolute difference (Davg) are given. These descriptors quantify the agreement between EEM model charges and QM charges for molecules belonging to the reference sets RS1 and RS2, and for five further test molecules T1–T5. All quantities are given in elementary charges (1 e∼1.602×10−19 coulombs). The names of the parameter sets encode the reference set and atom classification scheme based on which they were developed (RS1-E, RS1-EX, RS2-E, RS2-EX). Good agreement between QM and EEM charges was found for all data sets, as Ravg is close to 1, and RMSDavg and Davg are minimal. Calibrations that used the coarse atom type classification ‘E’ gave a similarly good agreement as those where the more detailed classification scheme ‘EX’ was used.
Mentions: Overall, the results in Figure 3 suggested that the finer grained atom classification scheme ‘EX’ only modestly improved the accuracy compared to the scheme ‘E’ based on chemical elements alone. The good agreement between QM and EEM charges for all data sets suggested that both atom classification schemes can provide satisfactory calibration results. Moreover, our model was able to compute EEM atomic charges in less than 1 second for any of the reference or test molecules using our previously published implementation [39].

Bottom Line: The affinity of the Bax C-domain for its binding groove is decreased due to the Arg94-mediated abrogation of the Ser184-Asp98 interaction.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.

View Article: PubMed Central - PubMed

Affiliation: CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus