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Nat Chem Biol. 2013 Mar;9(3):163-8. doi: 10.1038/nchembio.1166. Epub 2013 Jan 20.

PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis.

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Abstract

Following DNA damage, nuclear p53 induces the expression of PUMA, a BH3-only protein that binds and inhibits the antiapoptotic BCL-2 repertoire, including BCL-xL. PUMA, unique among BH3-only proteins, disrupts the interaction between cytosolic p53 and BCL-xL, allowing p53 to promote apoptosis via direct activation of the BCL-2 effector molecules BAX and BAK. Structural investigations using NMR spectroscopy and X-ray crystallography revealed that PUMA binding induced partial unfolding of two α-helices within BCL-xL. Wild-type PUMA or a PUMA mutant incapable of causing binding-induced unfolding of BCL-xL equivalently inhibited the antiapoptotic BCL-2 repertoire to sensitize for death receptor-activated apoptosis, but only wild-type PUMA promoted p53-dependent, DNA damage-induced apoptosis. Our data suggest that PUMA-induced partial unfolding of BCL-xL disrupts interactions between cytosolic p53 and BCL-xL, releasing the bound p53 to initiate apoptosis. We propose that regulated unfolding of BCL-xL provides a mechanism to promote PUMA-dependent signaling within the apoptotic pathways.

PMID:
23340338
PMCID:
PMC3683295
DOI:
10.1038/nchembio.1166
[Indexed for MEDLINE]
Free PMC Article

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