Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL
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...
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doaj-7e4a674630de4e418b35ae6cebd4c4f72021-09-09T13:47:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-01229388938810.3390/ijms22179388Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xLVivek Tyagi0Victor Vasquez-Montes1J. Alfredo Freites2Alexander Kyrychenko3Douglas J. Tobias4Alexey S. Ladokhin5Department of Materials Science and Engineering, University of California, Irvine, CA 92697, USADepartment of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Chemistry, University of California, Irvine, CA 92697, USADepartment of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Chemistry, University of California, Irvine, CA 92697, USADepartment of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USAThe 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 α1 through α7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins.https://www.mdpi.com/1422-0067/22/17/9388Bcl-xLBCL-2 proteinsBH3-binding sitecardiolipinapoptotic regulationprotein–membrane interactions |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vivek Tyagi Victor Vasquez-Montes J. Alfredo Freites Alexander Kyrychenko Douglas J. Tobias Alexey S. Ladokhin |
spellingShingle |
Vivek Tyagi Victor Vasquez-Montes J. Alfredo Freites Alexander Kyrychenko Douglas J. Tobias Alexey S. Ladokhin Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL International Journal of Molecular Sciences Bcl-xL BCL-2 proteins BH3-binding site cardiolipin apoptotic regulation protein–membrane interactions |
author_facet |
Vivek Tyagi Victor Vasquez-Montes J. Alfredo Freites Alexander Kyrychenko Douglas J. Tobias Alexey S. Ladokhin |
author_sort |
Vivek Tyagi |
title |
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL |
title_short |
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL |
title_full |
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL |
title_fullStr |
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL |
title_full_unstemmed |
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL |
title_sort |
effects of cardiolipin on the conformational dynamics of membrane-anchored bcl-xl |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-08-01 |
description |
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 α1 through α7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins. |
topic |
Bcl-xL BCL-2 proteins BH3-binding site cardiolipin apoptotic regulation protein–membrane interactions |
url |
https://www.mdpi.com/1422-0067/22/17/9388 |
work_keys_str_mv |
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