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J Biol Chem. 2014 Jan 31;289(5):2537-51. doi: 10.1074/jbc.M113.526806. Epub 2013 Dec 11.

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

Author information

1
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 in BAK when the protein targets to the membrane and forms pores. The data showed that helices α1 and α6 disengage from the rest of the domain, leaving helices α2-α5 as a folded unit. Helices α2-α5 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 α3 and α5 helices. The results provide further insights into the organization of the BAK oligomeric pores by the BAK homodimers during mitochondrial apoptosis, enabling the proposal of a BAK-induced lipidic pore with the topography of a "worm hole."

KEYWORDS:

Apoptosis; Bak; Bax; Bcl-2; Cell Death; Electron Paramagnetic Resonance (EPR); Mitochondria; Oligomerization Interface; Spin Labeling

PMID:
24337568
PMCID:
PMC3908389
DOI:
10.1074/jbc.M113.526806
[Indexed for MEDLINE]
Free PMC Article

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