Organization of the mitochondrial apoptotic BAK pore: oligomerization of the BAK homodimers.

Aluvila S, Mandal T, Hustedt E, Fajer P, Choe JY, Oh KJ.

J Biol Chem. 2014 Jan 31;289(5):2537-51.

From the Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064.

 

Abstract

 

The multidomain pro-apoptotic Bcl-2 family proteins BAK and BAX are believed to form large oligomeric pores in the mitochondrial outer membrane during apoptosis. Formation of these pores results in the release of apoptotic factors including cytochrome c from the intermembrane space into the cytoplasm, where they initiate the cascade of events that lead to cell death. Using the site-directed spin labeling method of electron paramagnetic resonance (EPR) spectroscopy, we have determined the conformational changes that occur inBAK when the protein targets to the membrane and forms pores. The data showed that helices {Alpha}1 and {Alpha}6 disengage from the rest of the domain, leaving helices {Alpha}2-{Alpha}5 as a folded unit. Helices {Alpha}2-{Alpha}5 were shown to form a dimeric structure, which is structurally homologous to the recently reported BAX “BH3-in-groove homodimer.” Furthermore, the EPR data and a chemical cross-linking study demonstrated the existence of a hitherto unknown interface between BAK BH3-in-groove homodimers in the oligomeric BAK. This novel interface involves the C termini of {Alpha}3 and {Alpha}5 helices. The results provide further insights into the organization of the BAK oligomeric pores by the BAKhomodimers during mitochondrial apoptosis, enabling the proposal of a BAK-induced lipidic pore with the topography of a “worm hole.”

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