Context-dependent Bcl-2/bak interactions regulate lymphoid cell apoptosis

Haiming Dai, X. Wei Meng, Sun Hee Lee, Paula A. Schneider, Scott H Kaufmann

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The release of cytochrome c from mitochondria, which leads to activation of the intrinsic apoptotic pathway, is regulated by interactions of Bax and Bak with antiapoptotic Bcl-2 family members. The factors that regulate these interactions are, at the present time, incompletely understood. Recent studies showing preferences in binding between synthetic Bcl-2 homology domain 3 and antiapoptotic Bcl-2 family members in vitro have suggested that the antiapoptotic proteins Mcl-1 and Bcl-xL, but not Bcl-2, restrain proapoptotic Bak from inducing mitochondrial membrane permeabilization and apoptosis. Here we show that Bak protein has a much higher affinity than the 26-amino acid Bak Bcl-2 homology domain 3 for Bcl-2, that some naturally occurring Bcl-2 allelic variants have an affinity for full-length Bak that is only 3-fold lower than that of Mcl-1, and that endogenous levels of these Bcl-2 variants (which are as much as 40-fold more abundant than Mcl-1) restrain part of the Bak in intact lymphoid cells. In addition, we demonstrate that Bcl-2 variants can, depending on their affinity for Bak, substitute for Mcl-1 in protecting cells. Thus, the ability of Bcl-2 to protect cells from activated Bak depends on two important contextual variables, the identity of the Bcl-2 present and the amount expressed.

Original languageEnglish (US)
Pages (from-to)18311-18322
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number27
DOIs
StatePublished - Jul 3 2009

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bcl-2 Homologous Antagonist-Killer Protein
Mitochondria
Cytochromes c
Chemical activation
Lymphocytes
Apoptosis
Membranes
Amino Acids
Aptitude
Mitochondrial Membranes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Context-dependent Bcl-2/bak interactions regulate lymphoid cell apoptosis. / Dai, Haiming; Meng, X. Wei; Lee, Sun Hee; Schneider, Paula A.; Kaufmann, Scott H.

In: Journal of Biological Chemistry, Vol. 284, No. 27, 03.07.2009, p. 18311-18322.

Research output: Contribution to journalArticle

Dai, Haiming ; Meng, X. Wei ; Lee, Sun Hee ; Schneider, Paula A. ; Kaufmann, Scott H. / Context-dependent Bcl-2/bak interactions regulate lymphoid cell apoptosis. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 27. pp. 18311-18322.
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