The crystal structure of the mouse apoptosis-inducing factor AIF

Mate, M.J.; Ortiz-Lombardı́a, M.; Boitel, Brigitte; Haouz, Ahmed; Tello, Diana; Susin, Santos A.; Penninger, Josef; Kroemer, Guido; Alzari, Pedro M.

doi:10.1038/nsb793

Cited by 164 publications

(161 citation statements)

References 30 publications

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“…In the presence of Mg 2 þ , AIF also caused the formation of networks with intermolecular contact, when added to double-stranded, linearized DNA ( Figure 6A), suggesting protein-protein interactions between different AIF molecules. Such AIF-AIF protein interactions have been previously described, based on the crystallographic analysis of the protein (Mate et al, 2002;Ye et al, 2002). The preponderant AIF effects (binding and condensation) were absent when AIF was added to relaxed, circular DNA (not shown) and attenuated when AIF was probed on negatively supercoiled DNA ( Figure 6C).…”

Section: Molecular Model Of the Aif Interaction With Nucleic Acidssupporting

confidence: 70%

Physical interaction of apoptosis-inducing factor with DNA and RNA

et al. 2005

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to singlestranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well doublestranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/ DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells.

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Section: Molecular Model Of the Aif Interaction With Nucleic Acidssupporting

confidence: 70%

Physical interaction of apoptosis-inducing factor with DNA and RNA

et al. 2005

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“…AIF has two distinct functions based on specific binding regions: a putative DNA binding site for its role as transcription factor and a second site which confers oxido-reductase activity [13,31]. The localization of AIF in the cytoplasm without translocation to the nuclei at any age implies a role as an antioxidant in the organ of Corti.…”

Section: Discussionmentioning

confidence: 99%

Oxidative imbalance in the aging inner ear

Jiang

Talaska

Schacht

et al. 2007

Neurobiology of Aging

182

122

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The mammalian inner ear loses its sensory cells with advancing age, accompanied by a functional decrease in balance and hearing. This study investigates oxidant stress in the cochlea of aging male CBA/J mice. Glutathione-conjugated proteins, markers of H 2 O 2 -mediated oxidation, began to increase at 12 months of age; 4-hydroxynonenal and 3-nitrotyrosine, products of hydroxyl radical and peroxynitrite action, respectively, were elevated by 18 months. Immunoreactivity to these markers was stronger in the supporting cells (Deiters and pillar cells) than the sensory cells. It appeared later (23 months) in the nerve fibers of the spiral ganglion and in the stria vascularis and spiral ligament. Conversely, antioxidant proteins (AIF) and enzymes (SOD2) decreased by 18 months in the organ of Corti (including the sensory cells) and nerve fibers but not in the stria vascularis. These results suggest the presence of different reactive oxygen species and differential time courses of oxidative changes in individual tissues of the aging cochlea. An imbalance of redox status may be a component of age-related hearing loss.

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“…1 Since its discovery 10 years ago, the AIF protein has been characterized at the structural level, 2,3 and the AIF gene has been subjected to genetic manipulations in mice, flies, nematodes and yeast, revealing the phylogenetically conserved contribution of AIF to cell death in multiple systems. 4,5 After the mitochondrial import of the precursor AIF protein and the removal of its N-terminal 53 amino acids, which includes a mitochondrial localization sequence (MLS), the processed mature human AIF 62 kDa is inserted into the inner mitochondrial membrane, with the N-terminus facing the matrix and with the C-terminal catalytic domain exposed to the intermembrane space.…”

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confidence: 99%

A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2

et al. 2010

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Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity. Apoptosis-inducing factor (AIF) has initially been described as a mitochondrial intermembrane protein that is released from mitochondria under conditions of cell death induction and that can induce isolated nuclei to undergo nuclear shrinkage and chromatinolysis, two features that are classically associated with apoptosis. 1 Since its discovery 10 years ago, the AIF protein has been characterized at the structural level, 2,3 and the AIF gene has been subjected to genetic manipulations in mice, flies, nematodes and yeast, revealing the phylogenetically conserved contribution of AIF to cell death in multiple systems. 4,5 After the mitochondrial import of the precursor AIF protein and the removal of its N-terminal 53 amino acids, which includes a mitochondrial localization sequence (MLS), the processed mature human AIF 62 kDa is inserted into the inner mitochondrial membrane, with the N-terminus facing the matrix and with the C-terminal catalytic domain exposed to the intermembrane space. 6 The mitochondrial AIF protein is an NAD(P)H oxidase 7 whose local redox function is essential for optimal oxidative phosphorylation. 8 Knockdown, deletion or hypomorphic mutation of AIF (the harlequin or Hq mutation) reduces the expression of complex I subunits in the respiratory chain, 8 thereby provoking a mitochondriopathy that leads to progressive neurodegeneration, photoreceptor loss and cardiomyopathy. [9][10][11][12][13] The consistent finding that the targeting of AIF mostly affects the central nervous system (CNS) 9 might either be explained by the general tendency of complex I mitochondriopathies to manifest at the level of the CNS 14 and/or by an implication of AIF in the differentiation of neuronal cell p...

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The crystal structure of the mouse apoptosis-inducing factor AIF

Cited by 164 publications

References 30 publications

Physical interaction of apoptosis-inducing factor with DNA and RNA

Physical interaction of apoptosis-inducing factor with DNA and RNA

Oxidative imbalance in the aging inner ear

A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2

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