期刊
EMBO JOURNAL
卷 35, 期 2, 页码 208-236出版社
WILEY-BLACKWELL
DOI: 10.15252/embj.201591552
关键词
Apoptosis/Bcl-2 proteins; membrane permeabilization; mitochondrial membranes; oligomerization
资金
- NIH [R01GM062964, R01GM099752, P20GM104934, P20GM103639]
- OCAST [HR10-121]
- NSF [CHE-1415910]
- NLM [5T15LM007359]
- CIHR [FRN12517]
- National Science Foundation [ACI-1053575]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103639, R01GM099752, R01GM062964, P20GM104934] Funding Source: NIH RePORTER
- NATIONAL LIBRARY OF MEDICINE [T15LM007359] Funding Source: NIH RePORTER
- Direct For Mathematical & Physical Scien [1415910] Funding Source: National Science Foundation
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 alpha 5 helix was released into the MOM, the remaining interface with alpha 2, alpha 3, and alpha 4 helices was rearranged. Another dimer interface was formed inside the MOM by two intersected or parallel alpha 9 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, alpha 9 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 alpha 9 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 alpha 9 dimerization at the rim.
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