This C-terminal domain appears to be a dimerization domain of the mitochondrial apoptosis-inducing factor 1. protein. The domain also appears at the C-terminus of FAD-dependent pyridine nucleotide-disulfide oxidoreductases. Apoptosis inducing factor (AIF) is a bifunctional mitochondrial flavoprotein critical for energy metabolism and induction of caspase-independent apoptosis. On reduction with NADH, AIF undergoes dimerization and forms tight, long-lived FADH2-NAD charge-transfer complexes proposed to be functionally important.
Family alignment:
There are 1222 AIF_C domains in 1220 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing AIF_C domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with AIF_C domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing AIF_C domain in the selected taxonomic class.
Redox-linked conformational dynamics in apoptosis-inducing factor.
J Mol Biol. 2009; 390: 924-38
Display abstract
Apoptosis-inducing factor (AIF) is a bifunctional mitochondrial flavoproteincritical for energy metabolism and induction of caspase-independent apoptosis,whose exact role in normal mitochondria remains unknown. Upon reduction withNADH, AIF undergoes dimerization and forms tight, long-lived FADH(2)-NADcharge-transfer complexes (CTC) that are proposed to be functionally important.To obtain a deeper insight into structure/function relations and redox mechanism of this vitally important protein, we determined the X-ray structures of oxidizedand NADH-reduced forms of naturally folded recombinant murine AIF. Our structuresreveal that CTC with the pyridine nucleotide is stabilized by (i) pi-stackinginteractions between coplanar nicotinamide, isoalloxazine, and Phe309 rings; (ii)rearrangement of multiple aromatic residues in the C-terminal domain, likelyserving as an electron delocalization site; and (iii) an extensivehydrogen-bonding network involving His453, a key residue that undergoes aconformational switch to directly interact with and optimally orient thenicotinamide for charge transfer. Via the His453-containing peptide, redoxchanges in the active site are transmitted to the surface, promoting AIFdimerization and restricting access to a primary nuclear localization signalthrough which the apoptogenic form is transported to the nucleus. Structuralfindings agree with biochemical data and support the hypothesis that both normal and apoptogenic functions of AIF are controlled by NADH.
DNA binding is required for the apoptogenic action of apoptosis inducing factor.
Nat Struct Biol. 2002; 9: 680-4
Display abstract
The execution of apoptosis or programmed cell death comprises bothcaspase-dependent and caspase-independent processes. Apoptosis inducing factor(AIF) was identified as a major player in caspase-independent cell death. Itinduces 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 potentialat the AIF surface, although the calculated isoelectric point for the entireprotein is neutral. We show that recombinant AIF interacts with DNA in asequence-independent manner. In addition, in cells treated with an apoptoticstimulus, endogenous AIF becomes co-localized with DNA at an early stage ofnuclear morphological changes. Structure-based mutagenesis shows that DNA-bindingdefective mutants of AIF fail to induce cell death while retaining nucleartranslocation. The potential DNA-binding site identified from mutagenesis alsocoincides with computational docking of a DNA duplex. These observations suggest that AIF-induced nuclear apoptosis requires a direct interaction with DNA.
