ROLE OF CHARGE TRANSFER IN THE ACTIVATION OF PRO-APOPTOTIC REGULATORS BAX AND BAK
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| Rok publikování | 2012 |
| Druh | Další prezentace na konferencích |
| Citace | |
| Popis | The activation of the proteins Bak and Bax is essential for programmed cell death (apoptosis) [1]. When activated, Bax and Bak homo-oligomerize and form pores in the mitochondrial outer membrane, causing the release of proteins that execute cell death. Yet, it is unknown precisely how Bak and Bax activation leads to their oligomerization, and what biophysical processes lead to a change in their structure and function [2]. A better understanding of these processes would help to design better drugs for overcoming apoptosis resistance in cancer, or for mitigating hypersensitive apoptosis during neuro-degenerative and auto-immune diseases. We investigated the role of charge transfer for the process of Bak and Bax activation by employing a method to calculate atomic charges of quantum chemical quality in proteins [3]. We identified a charge transfer network that conveys activation information from the Bax activation site to the well distanced sites required for Bax oligomerization. Our results confirm ongoing speculations of allosteric sensing during Bax activation, and reveal that allosteric regulation in Bax is mediated by charge transfer. Moreover, we found that such a charge transfer network is also plausible in Bak. Finally, our charge profile analysis identified new structural elements in Bax and Bak that represent novel targets for modulating apoptosis. We discuss these results here, and show how a straightforward analysis based on atomic point charges can be correlated with biological investigations. |
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