5fs6: Difference between revisions
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==Crystal structure of the V243L mutant of human apoptosis inducing factor== | |||
<StructureSection load='5fs6' size='340' side='right'caption='[[5fs6]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5fs6]] is a 2 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=5FS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FS6 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fs6 OCA], [https://pdbe.org/5fs6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fs6 RCSB], [https://www.ebi.ac.uk/pdbsum/5fs6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fs6 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[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 == | |||
[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 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<ref>PMID:27178839</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Sevrioukova | <div class="pdbe-citations 5fs6" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cell death protein 3D structures|Cell death protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Sevrioukova I]] | |||