期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms22179388
关键词
Bcl-xL; BCL-2 proteins; BH3-binding site; cardiolipin; apoptotic regulation; protein-membrane interactions; molecular dynamics simulations
资金
- National Institutes of Health [R01 GM126778, R01GM116961]
The study demonstrates that the protonation state of the protein and the cardiolipin content of the membrane modulate the orientation of membrane-anchored Bcl-xL, affecting the exposure of its BH3-binding groove and thus its interaction with pro-apoptotic proteins.
The anti-apoptotic protein Bcl-xL regulates apoptosis by preventing the permeation of the mitochondrial outer membrane by pro-apoptotic pore-forming proteins, which release apoptotic factors into the cytosol that ultimately lead to cell death. Two different membrane-integrated Bcl-xL constructs have been identified: a membrane-anchored and a membrane-inserted conformation. Here, we use molecular dynamics simulations to study the effect of the mitochondrial specific lipid cardiolipin and the protein protonation state on the conformational dynamics of membrane-anchored Bcl-xL. The analysis reveals that the protonation state of the protein and cardiolipin content of the membrane modulate the orientation of the soluble head region (helices alpha 1 through alpha 7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins.
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