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5fs6

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Revision as of 07:34, 6 May 2020

Crystal structure of the V243L mutant of human apoptosis inducing factor

Structural highlights

5fs6 is a 2 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:	5fs7, 5fs8, 5fs9
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]

Publication Abstract from PubMed

The X-linked AIFM1 gene encodes mitochondrial apoptosis-inducing factor (AIF), an FAD-containing and NADH-specific oxidoreductase critically important for energy metabolism and execution of the caspase-independent cell death pathway. Several recently identified mutations in human AIFM1 lead to neurodegenerative disorders varying in severity and onset time. This study was undertaken to structurally and functionally characterize four pathologic variants of human AIF: V243L, G262S, G308E, and G338E. A strong correlation between the mutational effects on the AIF function and clinical phenotype was observed only for the G308E aberration, drastically damaging both the redox properties of AIF and mitochondrial respiration. In contrast, only minimal or mild changes were detected in the structure/function of AIF V243L and G338E, respectively, indicating that a marked decrease in their cellular expression likely triggers the disease. Alterations in the structure and redox activity of AIF G262S, on the other hand, were more severe than could be predicted based on the clinical phenotype. Together, the results of this and previous studies allow to conclude that the phenotypic variability and severity of the AIFM1-related disorders depend on which AIF feature is predominantly affected (i.e., cellular production level, structure, redox or apoptogenic function) and to what extent. Only a drastic decrease in the expression level or/and redox activity of AIF tends to cause an early and severe neurodegeneration, whereas less pronounced changes in the AIF properties could lead to a broad range of slowly progressive neurological disorders.

Structure/Function Relations in AIFM1 Variants Associated with Neurodegenerative Disorders.,Sevrioukova IF J Mol Biol. 2016 May 10. pii: S0022-2836(16)30141-3. doi:, 10.1016/j.jmb.2016.05.004. PMID:27178839^[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
↑ Sevrioukova IF. Structure/Function Relations in AIFM1 Variants Associated with Neurodegenerative Disorders. J Mol Biol. 2016 May 10. pii: S0022-2836(16)30141-3. doi:, 10.1016/j.jmb.2016.05.004. PMID:27178839 doi:http://dx.doi.org/10.1016/j.jmb.2016.05.004

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5fs6"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the V243L mutant of human apoptosis inducing factor==
-<StructureSection load='5fs6' size='340' side='right' caption='[[5fs6]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='5fs6' size='340' side='right'caption='[[5fs6]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5fs6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FS6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FS6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5fs6]] is a 2 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=5FS6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FS6 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=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5fs7|5fs7]], [[5fs8|5fs8]], [[5fs9|5fs9]]</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=5fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fs6 OCA], [http://pdbe.org/5fs6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fs6 RCSB], [http://www.ebi.ac.uk/pdbsum/5fs6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fs6 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fs6 OCA], [http://pdbe.org/5fs6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fs6 RCSB], [http://www.ebi.ac.uk/pdbsum/5fs6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fs6 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 5fs6" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cell death protein|Cell death protein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Sevrioukova, I]]
 [[Category: Flavoprotein]]
 [[Category: Mitochondria]]
 [[Category: Oxidoreductase]]

5fs6

From Proteopedia

Revision as of 07:34, 6 May 2020

Crystal structure of the V243L mutant of human apoptosis inducing factor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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