1m6i

Crystal Structure of Apoptosis Inducing Factor (AIF)Crystal Structure of Apoptosis Inducing Factor (AIF)

Structural highlights

1m6i is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1gv4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[AIFM1_HUMAN] Defects in AIFM1 are the cause of combined oxidative phosphorylation deficiency type 6 (COXPD6) [MIM:300816]. It is a mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting.^[1] ^[2]

Function

[AIFM1_HUMAN] Probable oxidoreductase that has a dual role in controlling cellular life and death; during apoptosis, it is translocated from the mitochondria to the nucleus to function as a proapoptotic factor in a caspase-independent pathway, while in normal mitochondria, it functions as an antiapoptotic factor via its oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis, and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner.^[3] ^[4] ^[5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

DNA binding is required for the apoptogenic action of apoptosis inducing factor.,Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H Nat Struct Biol. 2002 Sep;9(9):680-4. PMID:12198487^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2010 Apr 9;86(4):639-49. doi: 10.1016/j.ajhg.2010.03.002. Epub, 2010 Apr 1. PMID:20362274 doi:10.1016/j.ajhg.2010.03.002
↑ Berger I, Ben-Neriah Z, Dor-Wolman T, Shaag A, Saada A, Zenvirt S, Raas-Rothschild A, Nadjari M, Kaestner KH, Elpeleg O. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Mol Genet Metab. 2011 Dec;104(4):517-20. doi: 10.1016/j.ymgme.2011.09.020. Epub, 2011 Sep 24. PMID:22019070 doi:10.1016/j.ymgme.2011.09.020
↑ Kim JT, Kim KD, Song EY, Lee HG, Kim JW, Kim JW, Chae SK, Kim E, Lee MS, Yang Y, Lim JS. Apoptosis-inducing factor (AIF) inhibits protein synthesis by interacting with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g). FEBS Lett. 2006 Nov 27;580(27):6375-83. Epub 2006 Nov 3. PMID:17094969 doi:10.1016/j.febslet.2006.10.049
↑ Son YO, Jang YS, Heo JS, Chung WT, Choi KC, Lee JC. Apoptosis-inducing factor plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Apoptosis. 2009 Jun;14(6):796-808. doi: 10.1007/s10495-009-0353-7. PMID:19418225 doi:10.1007/s10495-009-0353-7
↑ Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2010 Apr 9;86(4):639-49. doi: 10.1016/j.ajhg.2010.03.002. Epub, 2010 Apr 1. PMID:20362274 doi:10.1016/j.ajhg.2010.03.002
↑ Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H. DNA binding is required for the apoptogenic action of apoptosis inducing factor. Nat Struct Biol. 2002 Sep;9(9):680-4. PMID:12198487 doi:10.1038/nsb836

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2010 Apr 9;86(4):639-49. doi: 10.1016/j.ajhg.2010.03.002. Epub, 2010 Apr 1. PMID:20362274 doi:10.1016/j.ajhg.2010.03.002

[2] Berger I, Ben-Neriah Z, Dor-Wolman T, Shaag A, Saada A, Zenvirt S, Raas-Rothschild A, Nadjari M, Kaestner KH, Elpeleg O. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Mol Genet Metab. 2011 Dec;104(4):517-20. doi: 10.1016/j.ymgme.2011.09.020. Epub, 2011 Sep 24. PMID:22019070 doi:10.1016/j.ymgme.2011.09.020

[3] Kim JT, Kim KD, Song EY, Lee HG, Kim JW, Kim JW, Chae SK, Kim E, Lee MS, Yang Y, Lim JS. Apoptosis-inducing factor (AIF) inhibits protein synthesis by interacting with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g). FEBS Lett. 2006 Nov 27;580(27):6375-83. Epub 2006 Nov 3. PMID:17094969 doi:10.1016/j.febslet.2006.10.049

[4] Son YO, Jang YS, Heo JS, Chung WT, Choi KC, Lee JC. Apoptosis-inducing factor plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Apoptosis. 2009 Jun;14(6):796-808. doi: 10.1007/s10495-009-0353-7. PMID:19418225 doi:10.1007/s10495-009-0353-7

[5] Ghezzi D, Sevrioukova I, Invernizzi F, Lamperti C, Mora M, D'Adamo P, Novara F, Zuffardi O, Uziel G, Zeviani M. Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2010 Apr 9;86(4):639-49. doi: 10.1016/j.ajhg.2010.03.002. Epub, 2010 Apr 1. PMID:20362274 doi:10.1016/j.ajhg.2010.03.002

[6] Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H. DNA binding is required for the apoptogenic action of apoptosis inducing factor. Nat Struct Biol. 2002 Sep;9(9):680-4. PMID:12198487 doi:10.1038/nsb836

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