The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl-xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain ceramides that are elevated early in apoptosis, whereas short-chain ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes.
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July 2012
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Research Article|
June 15 2012
Bax and Bcl-xL exert their regulation on different sites of the ceramide channel
Meenu N. Perera
;
Meenu N. Perera
*Department of Biology, University of Maryland, College Park, MD 20742, U.S.A.
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Shang H. Lin
;
Shang H. Lin
*Department of Biology, University of Maryland, College Park, MD 20742, U.S.A.
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Yuri K. Peterson
;
Yuri K. Peterson
†Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29403, U.S.A.
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Alicja Bielawska
;
Alicja Bielawska
‡Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29403, U.S.A.
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Zdzislaw M. Szulc
;
Zdzislaw M. Szulc
‡Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29403, U.S.A.
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Robert Bittman
;
Robert Bittman
§Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, NY 11367, U.S.A.
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Marco Colombini
Marco Colombini
1
*Department of Biology, University of Maryland, College Park, MD 20742, U.S.A.
1To whom correspondence should be addressed (email colombini@umd.edu).
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Biochem J (2012) 445 (1): 81–91.
Article history
Received:
November 29 2011
Revision Received:
April 09 2012
Accepted:
April 11 2012
Accepted Manuscript online:
April 11 2012
Citation
Meenu N. Perera, Shang H. Lin, Yuri K. Peterson, Alicja Bielawska, Zdzislaw M. Szulc, Robert Bittman, Marco Colombini; Bax and Bcl-xL exert their regulation on different sites of the ceramide channel. Biochem J 1 July 2012; 445 (1): 81–91. doi: https://doi.org/10.1042/BJ20112103
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