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| | <StructureSection load='4bur' size='340' side='right'caption='[[4bur]], [[Resolution|resolution]] 2.88Å' scene=''> | | <StructureSection load='4bur' size='340' side='right'caption='[[4bur]], [[Resolution|resolution]] 2.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bur]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BUR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BUR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bur]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BUR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bv6|4bv6]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bur OCA], [https://pdbe.org/4bur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bur RCSB], [https://www.ebi.ac.uk/pdbsum/4bur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bur ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bur OCA], [http://pdbe.org/4bur PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bur RCSB], [http://www.ebi.ac.uk/pdbsum/4bur PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bur ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN]] Defects in AIFM1 are the cause of combined oxidative phosphorylation deficiency type 6 (COXPD6) [MIM:[http://omim.org/entry/300816 300816]]. It is a mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting.<ref>PMID:20362274</ref> <ref>PMID:22019070</ref> | + | [[https://www.uniprot.org/uniprot/AIFM1_HUMAN AIFM1_HUMAN]] Defects in AIFM1 are the cause of combined oxidative phosphorylation deficiency type 6 (COXPD6) [MIM:[https://omim.org/entry/300816 300816]]. It is a mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting.<ref>PMID:20362274</ref> <ref>PMID:22019070</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AIFM1_HUMAN 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.<ref>PMID:17094969</ref> <ref>PMID:19418225</ref> <ref>PMID:20362274</ref> | + | [[https://www.uniprot.org/uniprot/AIFM1_HUMAN 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.<ref>PMID:17094969</ref> <ref>PMID:19418225</ref> <ref>PMID:20362274</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The apoptosis-inducing factor (AIF) is a mitochondrial-flavoprotein that, after cell death induction, is distributed to the nucleus to mediate chromatinolysis. In mitochondria, AIF is present in a monomer-dimer equilibrium that after reduction by NADH gets displaced toward the dimer. The crystal structure of the human AIF (hAIF):NAD(H)-bound dimer revealed one FAD and, unexpectedly, two NAD(H) molecules per protomer. A 1:2 hAIF:NAD(H) binding stoichiometry was additionally confirmed in solution by using surface plasmon resonance. The here newly discovered NAD(H)-binding site includes residues mutated in human disorders, and accommodation of the coenzyme in it requires restructuring of a hAIF portion within the 509-560 apoptogenic segment. Disruption of interactions at the dimerization surface by production of the hAIF E413A/R422A/R430A mutant resulted in a nondimerizable variant considerably less efficiently stabilizing charge-transfer complexes upon coenzyme reduction than WT hAIF. These data reveal that the coenzyme-mediated monomer-dimer transition of hAIF modulates the conformation of its C-terminal proapoptotic domain, as well as its mechanism as reductase. These observations suggest that both the mitochondrial and apoptotic functions of hAIF are interconnected and coenzyme controlled: a key information in the understanding of the physiological role of AIF in the cellular life and death cycle.
| + | |
| - | | + | |
| - | Structural insights into the coenzyme mediated monomer-dimer transition of the pro-apoptotic apoptosis inducing factor.,Ferreira P, Villanueva R, Martinez-Julvez M, Herguedas B, Marcuello C, Fernandez-Silva P, Cabon L, Hermoso JA, Lostao A, Susin SA, Medina M Biochemistry. 2014 Jul 1;53(25):4204-15. doi: 10.1021/bi500343r. Epub 2014 Jun, 20. PMID:24914854<ref>PMID:24914854</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4bur" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Apoptosis-inducing factor|Apoptosis-inducing factor]] | | *[[Apoptosis-inducing factor|Apoptosis-inducing factor]] |
| - | *[[Cell death protein|Cell death protein]] | + | *[[Cell death protein 3D structures|Cell death protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ferreira, P]] | + | [[Category: Ferreira P]] |
| - | [[Category: Herguedas, B]] | + | [[Category: Herguedas B]] |
| - | [[Category: Hermoso, J A]] | + | [[Category: Hermoso JA]] |
| - | [[Category: Martinez-Julvez, M]] | + | [[Category: Martinez-Julvez M]] |
| - | [[Category: Medina, M]] | + | [[Category: Medina M]] |
| - | [[Category: Villanueva, R]] | + | [[Category: Villanueva R]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Mitochondria]]
| + | |
| - | [[Category: Nuclear chromatinolysis]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
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]
See Also
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
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