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EMBO J. 2016 Jan 18;35(2):208-36. doi: 10.15252/embj.201591552. Epub 2015 Dec 23.

BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes.

Author information

1
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
2
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
3
Biological Sciences, Sunnybrook Research Institute, Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
4
Department of Chemistry, University of Vermont, Burlington, VT, USA.
5
Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
6
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
7
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA jialing-lin@ouhsc.edu.

Abstract

Pro-apoptotic Bax induces mitochondrial outer membrane permeabilization (MOMP) by forming oligomers through a largely undefined process. Using site-specific disulfide crosslinking, compartment-specific chemical labeling, and mutational analysis, we found that activated integral membrane Bax proteins form a BH3-in-groove dimer interface on the MOM surface similar to that observed in crystals. However, after the α5 helix was released into the MOM, the remaining interface with α2, α3, and α4 helices was rearranged. Another dimer interface was formed inside the MOM by two intersected or parallel α9 helices. Combinations of these interfaces generated oligomers in the MOM. Oligomerization was initiated by BH3-in-groove dimerization, without which neither the other dimerizations nor MOMP occurred. In contrast, α9 dimerization occurred downstream and was required for release of large but not small proteins from mitochondria. Moreover, the release of large proteins was facilitated by α9 insertion into the MOM and localization to the pore rim. Therefore, the BH3-in-groove dimerization on the MOM nucleates the assembly of an oligomeric Bax pore that is enlarged by α9 dimerization at the rim.

KEYWORDS:

Apoptosis/Bcl‐2 proteins; membrane permeabilization; mitochondrial membranes; oligomerization

PMID:
26702098
PMCID:
PMC4718459
DOI:
10.15252/embj.201591552
[Indexed for MEDLINE]
Free PMC Article

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