Pro-apoptotic Cleavage Products of Bcl-xL Form Cytochrome c-conducting Pores in Pure Lipid Membranes

Gorka Basañez, Jun Zhang, B. Nelson Chau, Grigory I. Maksaev, Vadim A. Frolov, Teresa A. Brandt, Jennifer Burch, J. Marie Hardwick, Joshua Zimmerberg

Research output: Contribution to journalArticlepeer-review

Abstract

During apoptotic cell death, cells usually release apoptogenic proteins such as cytochrome c from the mitochondrial intermembrane space. If Bcl-2 family proteins induce such release by increasing outer mitochondrial membrane permeability, then the pro-apoptotic, but not anti-apoptotic activity of these proteins should correlate with their permeabilization of membranes to cytochrome c. Here, we tested this hypothesis using pro-survival full-length Bcl-xL and pro-death Bcl-xL cleavage products (ΔN61Bcl-xL and ΔN76Bcl-xL). Unlike Bcl-x L, ΔN61Bcl-xL and ΔN76Bcl-xL caused the release of cytochrome c from mitochondria in vivo and in vitro. Recombinant ΔN61Bcl-xL and ΔN76Bcl-xL, as well as Bcl-xL, cleaved in situ by caspase 3-possessed intrinsic pore-forming activity as demonstrated by their ability to efficiently permeabilize pure lipid vesicles. Furthermore, only ΔN61Bcl-xL and ΔN76Bcl-xL, but not Bcl-xL, formed pores large enough to release cytochrome c and to destabilize planar lipid bilayer membranes through reduction of pore line tension. Because Bcl-xL and its C-terminal cleavage prod. ucts bound similarly to lipid membranes and formed oligomers of the same size, neither lipid affinity nor protein-protein interactions appear to be solely responsible for the increased membrane-perturbing activity elicited by Bcl-xL cleavage. Taken together, these data are consistent with the hypothesis that Bax-like proteins oligomerize to form lipid-containing pores in the outer mitochondrial membrane, thereby releasing intermembrane apoptogenic factors into the cytosol.

Original languageEnglish (US)
Pages (from-to)31083-31091
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number33
DOIs
StatePublished - Aug 17 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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