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doi: 10.1242/10.1242/jcs.00210

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Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?

¹ Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
² Department of Biology, University of Rome Tor Vergata, Roma, Italy

View larger version (30K): [in a new window]   Fig. 1. Phylogenetic tree of the common pyridine nuleotide disulphide oxidoreductase domain. The limits are taken on the mouse AIF gene (offical name PCD8_MOUSE, positions 120 to 477). The alignment and the phylogenetc tree have been performed with the Clustal program, and the figure was produced with Treeview. Species names have been abbreviated according to the Swiss-Prot nomenclature. Upper case letters indicate the Swiss-Prot identification, while lower case letters correspond to mnemonic identification. aif_anoga, aif_tetng, AIF (Tetraodon nigroviridis); aif_caeel, Q9U229 (C. elegans); aif_disdi, Q9GRX6, AIF (D. discoideum); aif_fugru, AIF (Fugu rubripes); amid_human, AMID (Homo sapiens); amid_mouse, AMID (Mus musculus); dhna_synp7, Q935X8 (Synechococcus sp.); DLD1_PSEPU, dihydrolipoamide dehydrogenase (Pseudomonas putida); DLDH_BACST, dihydrolipoamide dehydrogenase (Bacillus stearothermophilus); DLDH_PEA, dihydrolipoamide dehydrogenase (Pisum sativum); DLDH_PSEFL, oxoglutarate dehydrogenase complex (Pseudomonas fluorescens); DLDH_YEAST, dihydrolipoamide dehydrogenase (Saccharomyces cerevisiae); EAA12325, (Anopheles gambiae); ferre_pseusp, Q52437, ferredoxin reductase (Pseudomonas sp.); ferre_rhoer, O69367, ferredoxin reductase (Rhodococcus erythropolis); ferre_xenla, O42346, neurula-specific ferrodoxin reductase-like protein (Xenopus laevis); FLRR_ECOLI, flavorubredoxin reductase (E. coli); GSHR_ECOLI, glutathione reductase (E. coli); GSHR_HUMAN, glutathione reductase (H. sapiens); gshr_rat, O89049, thioredoxin reductase (R. norvegicus); hyp_anasp, Q8YRY5 (Anabaena sp.); hyp_caeel, Q19655 (C. elegans); hyp_drome, O77266 (D. melanogaster); hyp_human, Q96NN9 (H. sapiens); hyp1_arath, Q9LXP4 (Arabidopsis thaliana); hyp2_arath, Q9C574 (A. thaliana); mdha_mescr, Q93YG1, monodehydroascorbate reductase (Mesembryanthemum crystallinum); mdha_orysa, Q8S3R2, putative cytosolic monodehydroascorbate reductase (Oryza sativa); mdha-arath, P92947, monodehydroascorbate reductase (A. thaliana); nadhd_anasp, Q8YPU6, NADH dehydrogenase (Anabaena sp.); nadhox_aquae, O67007, NADH oxidase (Aquifex aeolicus); nadhox_enthi, Q8WR54, NADH oxidase (Entamoeba histolytica).; nadhox_pyrab, Q9V0X9, NADH oxidase (Pyrococcus abyssi); nadhox_pyrfur, Q8U0Q3, NADH oxidase (Pyrococcus furiosus); NAPE_ENTFA, NADH peroxidase (Enterococcus faecalis); nitre_ecoli, Q8XEE3, nitrite reductase (NAD(P)H) subunit. (E. coli); nitre_picpa, Q9URM3, nitrite reductase (Pichia angusta); om_neime, OUTER MEMBRANE PROTEIN (Neisseria meningitidis); PCD8_DROME, AIF (Drosophila melanogaster); PCD8_HUMAN, AIF (H. sapiens); PCD8_MOUSE, AIF (Mus musculus); PCD8_RAT, AIF (Rattus norvegicus); PsbAa_rhopa, Q9XDW7 (Rhodopseudomonas palustris); rubre_rhilo, Q98BL3, rubredoxin reductase (Rhizobium loti); TYTR_CRIFA, trypanothione reductase (Crithidia fasciculata); TYTR_TRYCR, trypanothione reductase (Trypanosoma cruzi).

View larger version (80K): [in a new window]   Fig. 2. Functional domain organization of AIF. (a) Domains of AIF important for its oxidoreductase function. The FAD-binding and NADH-binding domains of AIF are depicted. In addition, an AIF-specific insertion (509-559) not found in other proteins of this family has been marked. Residues whose mutation affect FAD binding (Lys176, Glu313, Cus255-Gly260) are indicated. (b) Domains of AIF important for its apoptogenic function. Amino acids with positive charges exposed at the surface are indicated. The surface-exposed area of AIF recognized by a neutralizing antibody (151-200) is also marked. Gain-of-function mutations are indicated in blue, while loss-of-function mutations are in red. Note that this model has been built on the crystal structure of mouse AIF, while data on gain-of-function and loss-of-function mutations of positively charged surface arginines and lysines have been obtained from human AIF.

View larger version (110K): [in a new window]   Fig. 3. Mitochondrio-nuclear AIF translocation in the interdigital cells of the mouse embryo. (A) Persistent interdigital web from an Apaf1-/- embryo (E15.5). The interdigital webs are marked by a dashed line. Holes are forming by Apaf1-independent death. The red insert is shown at higher magnification in B. (B) Double staining with Hoechst 33324 (blue) and an anti-AIF antibody (red). (C-E) Further magnification of the rectangle shown in B. Note that condensed nuclei (D) contain AIF (E) within the same cells (overlay in C). Arrows in C, D and E point to the same dying cells.