European Biophysics Journal

, Volume 38, Issue 7, pp 941–960

Activation of Bax by joint action of tBid and mitochondrial outer membrane: Monte Carlo simulations

Original Paper

DOI: 10.1007/s00249-009-0475-4

Cite this article as:
Veresov, V.G. & Davidovskii, A.I. Eur Biophys J (2009) 38: 941. doi:10.1007/s00249-009-0475-4

Abstract

The mitochondrial pathway of apoptosis proceeds when molecules, such as cytochrome c, sequestered between the outer and inner mitochondrial membranes are released to the cytosol by mitochondrial outer membrane (MOM) permeabilization. Bax, a member of the Bcl-2 protein family, plays a pivotal role in mitochondrion-mediated apoptosis. In response to apoptotic stimuli, Bax integrates into the MOM, where it mediates the release of cytochrome c from the intermembrane space into the cytosol, leading to caspase activation and cell death. The pro-death action of Bax is regulated by interactions with both other prosurvival proteins, such as tBid, and the MOM, but the exact mechanisms remain largely unclear. Here, the mechanisms of integration of Bax into a model membrane mimicking the MOM were studied by Monte Carlo simulations preceded by a computer prediction of the docking of tBid with Bax. A novel model of Bax activation by tBid was predicted by the simulations. In this model, tBid binds to Bax at an interaction site formed by Bax helices α1, α2, α3 and α5 leading, due to interaction of the positively charged N-terminal fragment of tBid with anionic lipid headgroups, to Bax reorientation such that a hydrogen-bonded pair of residues, Asp98 and Ser184, is brought into close proximity with negatively charged lipid headgroups. The interaction with these headgroups destabilizes the hydrogen bond which results in the release of helix α9 from the Bax-binding groove, its insertion into the membrane, followed by insertion into the membrane of the α5–α6 helical hairpin.

Keywords

Apoptosis Bax tBid Mitochondria Monte Carlo simulations 

Supplementary material

249_2009_475_MOESM1_ESM.doc (1.6 mb)
Supplementary material (DOC 1653 kb)

Copyright information

© European Biophysical Societies' Association 2009

Authors and Affiliations

  1. 1.Department of Cell BiophysicsInstitute of Biophysics and Cell EngineeringMinskBelarus