Bcl-XL mutations suppress cellular sensitivity to ...[J Biol Chem. 2004]

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1: J Biol Chem. 2004 Jan 16;279(3):2159-65. Epub 2003 Oct 8. Links

Bcl-XL mutations suppress cellular sensitivity to antimycin A.

Manion MK, O'Neill JW, Giedt CD, Kim KM, Zhang KY, Hockenbery DM.

Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Cells expressing high levels of the BCL-X(L) anti-apoptotic protein are preferentially killed by the mitochondrial inhibitor antimycin A (AA). Computational modeling predicts a binding site for AA in the extended hydrophobic groove on BCL-X(L), previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-X(L) hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD(50) of AA for cells expressing BCL-X(L) mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-X(L) is a principal target mediating AA cytotoxicity.

PMID: 14534311 [PubMed - indexed for MEDLINE]

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[Biochim Biophys Acta. 2004]
Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3.
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[Nat Cell Biol. 2001]
Studies of the interaction of substituted mutants of BAX with yeast mitochondria reveal that the C-terminal hydrophobic alpha-helix is a second ART sequence and plays a role in the interaction with anti-apoptotic BCL-xL.
J Biol Chem. 2004 Dec 10; 279(50):52566-73. Epub 2004 Sep 30.

[J Biol Chem. 2004]
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[Metab Eng. 2003]
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[Semin Oncol. 2003]
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Cited by 2 PubMed Central articles

Molecular basis of the interaction between the antiapoptotic Bcl-2 family proteins and the proapoptotic protein ASPP2.
Katz C, Benyamini H, Rotem S, Lebendiker M, Danieli T, Iosub A, Refaely H, Dines M, Bronner V, Bravman T, et al. Proc Natl Acad Sci U S A. 2008 Aug 26; 105(34):12277-82. Epub 2008 Aug 21.

[Proc Natl Acad Sci U S A. 2008]
Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin.
Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ. Blood. 2005 Sep 1; 106(5):1857-63. Epub 2005 May 17.

[Blood. 2005]

Structures reported by this article

Human Bcl-Xl Containing A Phe To Leu Mutation At Position 146

PDB: 1R2I

Source: Homo sapiens

Method: X-Ray Diffraction | Resolution: 2 Å
» See all 5 structures...

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