Bax and Bcl-xL exert their regulation on different sites of the ceramide channel

Meenu N. Perera, Shang H. Lin, Yuri K. Peterson, Alicja Bielawska, Zdzislaw M. Szulc, Robert Bittman, Marco Colombini

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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, BclxL 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 A 3, 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.

Original languageEnglish (US)
Pages (from-to)81-91
Number of pages11
JournalBiochemical Journal
Volume445
Issue number1
DOIs
StatePublished - Jul 1 2012

Keywords

  • 2-methoxyantimicin A
  • ABT-263
  • ABT-737
  • Apoptosis
  • Bcl-2 family protein
  • Ceramide analogue
  • Ceramide channel
  • Mitochondrion

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