DNA binding is required for the apoptogenic action of apoptosis inducing factor |
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Authors: | Ye Hong Cande Celine Stephanou Nicolas C Jiang Sulin Gurbuxani Sundeep Larochette Nathanael Daugas Eric Garrido Carmen Kroemer Guido Wu Hao |
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Affiliation: | Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. |
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Abstract: | 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 A 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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