Nature Structural Biology9, 680 - 684 (2002)
Published online: 19 August 2002; | doi:10.1038/nsb836
DNA binding is required for the apoptogenic action of apoptosis
inducing factor
Hong Ye1, Celine Cande2, Nicolas C. Stephanou1, Sulin Jiang1, Sundeep Gurbuxani3, Nathanael Larochette2, Eric Daugas2, Carmen Garrido3, Guido Kroemer2
& Hao Wu1
1
Department of Biochemistry, Weill Medical College
of Cornell University, 1300 York Avenue, New
York, New York 10021, USA.
2
Centre National de la Recherche Scientifique,
UMR1599, Institut Gustave Roussy, 39 rue Camille
Desmoulins, F-94805 Villejuif,
France.
3
INSERM U-517, Faculty of Medicine and
Pharmacy, 7 Boulevard Jeanne d'Arc, 21033
Dijon, France.
The execution of apoptosis or programmed cell death comprises both
caspase-dependent and caspase-independent processes. Apoptosis inducing factor
(AIF) was identified as a major player in caspase-independent cell death. It
induces chromatin condensation and initial DNA cleavage via an unknown
molecular mechanism. Here we report the crystal structure of human AIF at 1.8
Å resolution. The structure reveals the presence of a strong positive
electrostatic potential at the AIF surface, although the calculated isoelectric
point for the entire protein is neutral. We show that recombinant AIF interacts
with DNA in a sequence-independent manner. In addition, in cells treated with
an apoptotic stimulus, endogenous AIF becomes co-localized with DNA at an early
stage of nuclear morphological changes. Structure-based mutagenesis shows that
DNA-binding defective mutants of AIF fail to induce cell death while retaining
nuclear translocation. The potential DNA-binding site identified from
mutagenesis also coincides with computational docking of a DNA duplex. These
observations suggest that AIF-induced nuclear apoptosis requires a direct
interaction with DNA.
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