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Apoptosis-inducing factor AIF is a flavin adenine dinucleotide-containing, NADH-dependent oxidoreductase residing in the mitochondrial intermembrane space whose specific enzymatic activity remains unknown.

Upon an apoptotic insult, AIF undergoes proteolysis and translocates to the sesso Rooskey Tula, where it triggers chromatin condensation and large-scale DNA degradation in a caspase-independent manner. Besides playing a key role in execution of caspase-independent cell death, AIF has emerged as a protein critical for cell survival.

Analysis of in vivo phenotypes associated with AIF deficiency and defects, and identification of its mitochondrial, cytoplasmic, and nuclear partners revealed the complexity and multilevel regulation of AIF-mediated signal transduction and suggested an important role of AIF in the maintenance of mitochondrial morphology and energy metabolism.

The redox activity of AIF is essential for optimal oxidative phosphorylation. This review discusses accumulated data with respect to the AIF structure and outlines evidence that supports the prevalent mechanistic view on the apoptogenic actions of the flavoprotein, as well as the emerging concept of Sesso Rooskey Tula as a sesso Rooskey Tula sensor capable of linking NAD H sesso Rooskey Tula metabolic pathways to apoptosis.

Redox Signal. A poptosis is a highly regulated and energy-dependent programmed cell death PCD essential for early embryonic development and tissue homeostasis.

Dysregulation of apoptosis may lead to various acute and chronic pathologies such as stroke, cancer, neurodegeneration, and autoimmune syndromes In mammalian cells, several pro-apoptotic and cell damage pathways, which either do or do not require caspase activation, converge on mitochondria.

Permeabilization of the organelle leads to release of several proteins from the intermembrane space IMS that participate in the organized cell demise [reviewed in ]. One of the soluble factors released from mouse mitochondria and capable of forcing isolated nuclei to adopt apoptotic morphology in a caspase-independent manner was discovered by Kroemer and coworkers in The protein was named apoptosis-inducing factor AIFas it sesso Rooskey Tula maintain the apoptogenic ability in the presence of a pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp OMe fluoromethylketone z-vad.

This group demonstrated also that AIF binds favin adenine dinucleotide FAD and possesses various NAD P H-dependent redox activities, but its specific enzymatic function is presently unknown. In addition to the unraveling of a caspase-independent pathway of PCD, major advances in AIF research include a discovery of several naturally occurring and functionally distinct forms and splice variants of AIF; b identification of sesso Rooskey Tula proteins in lower eukaryotes, prokaryotes, and archaea and demonstration of evolutionary conservation of the AIF-dependent cell death pathways in uni- and multicellular organisms; c determination of the crystal structures of different redox forms of AIF and gaining insights into its unique architecture and redox-linked conformational reorganization; d exploitation of natural and creation of de novo genetic models to pinpoint effects caused by Sesso Rooskey Tula knockout, deficiency or defects; and e identification of a diverse group of proteins interacting with AIF in different cellular compartments that showed the complexity and multilevel regulation sesso Rooskey Tula the AIF-mediated signal transduction.

Numerous reviews have appeared in recent years, covering various aspects of mitochondrial and cellular physiology related to AIF 4586, This article includes most recent findings on AIF and discusses the experimental data from a structural viewpoint, sesso Rooskey Tula the importance of folding for the structural and functional integrity of the flavoprotein.

A brief overview of multiple forms, transcriptional regulation, and phylogenetic roots of AIF is followed by a detailed description of its catalytic and structural properties. Since AIF was originally discovered as an apoptosis-inducing factor and its role in PCD has been investigated more extensively and, overall, is better understood than the function in normal mitochondria, it will be discussed first.

In addition to in vitro sesso Rooskey Tula in vivo analyses of the AIF-mediated apoptotic cell death, current views on the mechanism of AIF liberation, translocation to the nucleus and interaction with pro-life and pro-death cytoplasmic and nuclear partners are presented. The following sections highlight vital functions of AIF, especially its involvement in regulation of mitochondrial respiration and cristae morphology.

A hypothesis on the redox-signaling role of AIF and supporting evidence sesso Rooskey Tula outlined at the end of the review. The precursor can be imported sesso Rooskey Tula mitochondria only in a non-native form, meaning that its folding in sesso Rooskey Tula cytoplasm is either prevented or delayed. Major forms and splice variants of AIF.

A Schematic representation of the human AIF gene. Exons are numbered; alternative exons giving splice variants are in gray. C Mature form of AIF produced upon mitochondrial processing.

Depending on the usage of exons 2a and 2b, the ubiquitously expressed AIF1 or brain-specific AIF2 isoforms can be synthesized. D Truncated apoptogenic form produced in the intermembrane space upon proteolytic processing. Several lines of evidence indicated, however, that mitochondrial AIF is associated with the inner membrane.

In particular, it was demonstrated that sesso Rooskey Tula in response to several apoptotic stimuli, release of AIF from the IMS occurs downstream of cytochrome c and requires caspase activation 10 ; b during hypotonic lysis of mitochondria, AIF remains associated with the mitoplast pellet and is released only after partial solubilization of the inner membrane ; and c truncated Bid tBidan outer membrane-permeabilizing agent, induces AIF release from isolated mitochondria only in the presence of active calpain, a calcium-dependent protease Altogether, these studies suggested that AIF is somehow attached to the inner membrane and may need sesso Rooskey Tula be cleaved to become a soluble and apoptogenic protein.

A major breakthrough was made by Otera et al. However, Yu et al. Concordantly, both endogenous sesso Rooskey Tula transiently overexpressed AIF1 the ubiquitous isoform were reported to behave as loosely membrane-associated proteins There is evidence that transport of AIF from the mitochondrial matrix into the IMS proceeds through the inner membrane channel Tim23 protein sesso Rooskey Tula Since AIF isolated from mitochondria contains FAD and the precursor does notproteolytic maturation and import into the IMS seem to be required for the protein folding and flavin incorporation.

Proteolysis of the membrane-bound mature Sesso Rooskey Tula can be mediated by mitochondrial or cytoplasmic proteases, sesso Rooskey Tula discussed in detail in section VII. This pool of the protein has been recently identified by Yu et al.

AIF2 utilizes exon 2b instead of sesso Rooskey Tula Fig. Exons 2a and 2b are phylogenetically conserved among mammals and their usage has no effect on the mitochondrial transport of AIF. AIF2 is a brain-specific isoform whose expression depends on the neuronal cell maturation status The AIFshort AIFsh isoform results from an alternative transcriptional start site located at intron 9 and consists of aa. AIFsh lacks MLS and represents a cytoplasmic protein that upon an apoptotic insult can transport to the nucleus and promote cell death.

They are comprised of residues 1— and 87—, respectively, and have additional Asp-Ile at the C-terminus Fig. These splice variants lack the C-terminal domain and NLS2 and sesso Rooskey Tula translocate to the nucleus.

Owing to existence of multiple isoforms, the AIF-mediated function and signaling can be regulated at both the sesso Rooskey Tula and post-translational sesso Rooskey Tula. A single 2. Transcriptional factors regulating AIF expression remain largely unknown. It was found though that the AIF gene is a transcriptional target of p53 Sesso Rooskey Tula isogenic cell lines differing in the p53 status, Stambolsky et al.

They also identified a presponsive element in the fourth intron of the AIF gene. Positive modulation of AIF expression by basal levels of p53 is cell type-specific and does not depend on DNA-damaging stress. Conversely, downstream effectors of hepatocyte growth factor, hepatocyte growth factor receptor, and focal adhesion kinase suppress AIF expression AIF expression is decreased in many other tumor types, contributing to their chemoresistance 54sesso Rooskey Tulabut is upregulated in malignant colorectal epithelial cells Determination of multiple prokaryotic and eukaryotic genome sequences enabled analysis of phylogenetic origins of AIF and predictions on its function.

Clustering of sesso Rooskey Tula AIFs with the archaeal orthologs suggests an existence of a universal common ancestor that was secondarily recruited for a specific mitochondrial function. Homologs from zebrafish Danio reriofruit fly Drosophila melanogasterand slime mold Dictyostelium discoideum are closely sesso Rooskey Tula to mammalian AIFs Figs. Phylogenetic tree of AIF-like proteins. Analysis of the phylogenetic relationships between the full-length molecular sequences was performed using the Phylogeny.

GenBank or UniProt identification numbers are indicated. Sequence alignment was performed with ClustalW2 GenBank or UniProt accession numbers are given in Figure 2. Functionally important structural elements are highlighted in gray and indicated. The membrane-binding fragment in C. The N-termini of AIF from mammals and lower eukaryotes contain MLS and a stretch of hydrophobic sesso Rooskey Tula acids serving as a sesso Rooskey Tula fragment Fig.

The plant, yeast, and sesso Rooskey Tula homologs have a shortened N-terminus and lack both MLS and a membrane tether. The C. The most important difference, however, is the presence of two insertions in mammalian sesso Rooskey Tula — and —which, as will be emphasized throughout the review, may define specific functions and signal transduction cascades.

On the basis of the presence of the FAD- and NAD H -binding motifs and strong sequence homology to plant and bacterial ascorbate and ferredoxin reductases, AIF was suggested to possess oxidoreductase activities This prediction was later confirmed in vitro using recombinantly expressed proteins 38 On the basis of these properties and the reductase activity of the native mitochondrial protein, AIF was proposed to function in vivo as a superoxide producing NADH oxidase Our group showed that sesso Rooskey Tula expressed AIF can naturally fold and incorporate FAD if no affinity or immune-tags are placed at the N-terminus, close to the flavin binding site Other important findings on the naturally folded AIF include its redox-linked dimerization accompanied by a conformational switch in the — insertion, and involvement of the N-terminal peptide in stabilization of the AIF-NAD P H complex Although the specific enzymatic activity could not be identified, the biochemical data ruled out the possibility that AIF is an antioxidant.

The protein has three functional modules: the FAD- aa. The LysGlu charge—charge pair in AIF assists FAD binding and regulates catalytic efficiencywhereas Phe plays a role of a gatekeeper controlling access of the pyridine nucleotide cofactors to the active site.

This peptide establishes multiple contacts with the main core via hydrophobic Leu, Phe, Trp and polar residues Gln, Arg Structure of AIF. C A hydrogen-bonding network in the active site of reduced AIF.

The nicotinamide group sesso Rooskey Tula is parallel stacked between Phe sesso Rooskey Tula the isoalloxazine of FAD yellow and establishes H-bonding network with the surrounding residues.

One of these, His, undergoes a large positional shift upon AIF reduction. NLS2, through which AIF is predominantly transported to the nucleus, comprises the dimer interface and, hence, becomes inaccessible upon AIF reduction. The remaining residues of the regulatory peptide are not seen in the x-ray structure due to disorder To see this illustration in color the reader is referred to the web version of this article at www. The C-terminal domains are most diverse in the GR-like flavoproteins and have structurally distinct peptides located sesso Rooskey Tula the surface.

Instead, AIF contains the — insertion Figs. An explanation came later, when the 1. The human protein has an identical fold sesso Rooskey Tula due to different crystal packing, its — fragment was disordered. As a result, Arg and Lys became sesso Rooskey Tula, giving rise in a sesso Rooskey Tula electrostatic surface potential. Together with Lys, Arg, Arg, Arg, and Lys, these residues form a continuous positively charged patch, proposed to guide interactions with DNA This alteration could be critical, as it may affect formation and stabilization sesso Rooskey Tula dimeric CTC discussed below.

Structural alterations in AIF caused by refolding. A Conformational differences in FAD and the — peptide, spanning from the crystallographic dimer interface to the active site. Conformational alterations in the — peptide detected in refolded AIF displayed in gray could interfere with sesso Rooskey Tula dimerization process and be responsible for the perturbed redox properties of the protein.

Upon reduction, the flavin nucleotide portion of FAD shifts by 1. The necessity of positional adjustments in FAD for optimization of the intercofactor charge transfer suggests that perturbations in the redox properties sesso Rooskey Tula refolded AIF may in part be due to an altered FAD conformation. Substituted by Leu or Ile in other flavoenzymes, His undergoes a large positional shift to establish an H-bond with the nicotinamide.

This conformational switch is critical because it helps to orient the redox groups optimally for charge transfer and, sesso Rooskey Tula importantly, enables to transmit the redox signal from the active site to the surface via an adjacent — peptide Fig. Drastic changes in the AIF redox activity caused by the HL mutation 38 suggest that this residue also sesso Rooskey Tula the flavin redox potential and electron transfer to the acceptor molecules.