Structural insights into the degradation of Mcl-1 induced by BH3 domains

Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6217-22. doi: 10.1073/pnas.0701297104.

Peter E Czabotar ¹, Erinna F Lee, Mark F van Delft, Catherine L Day, Brian J Smith, David C S Huang, W Douglas Fairlie, Mark G Hinds, Peter M Colman

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Affiliation

1 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.

PMID: 17389404 DOI: 10.1073/pnas.0701297104

Abstract

Apoptosis is held in check by prosurvival proteins of the Bcl-2 Family. The distantly related BH3-only proteins bind to and antagonize them, thereby promoting Apoptosis. Whereas binding of the BH3-only protein Noxa to prosurvival Mcl-1 induces Mcl-1 degradation by the Proteasome, binding of another BH3-only ligand, Bim, elevates Mcl-1 protein levels. We compared the three-dimensional structures of the complexes formed between BH3 Peptides of both Bim and Noxa, and we show that a discrete C-terminal sequence of the Noxa BH3 is necessary to instigate Mcl-1 degradation.

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