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| | <SX load='6nzu' size='340' side='right' viewer='molstar' caption='[[6nzu]], [[Resolution|resolution]] 3.20Å' scene=''> | | <SX load='6nzu' size='340' side='right' viewer='molstar' caption='[[6nzu]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nzu]] is a 10 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=6NZU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6NZU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nzu]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NZU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8Q1:S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl]+dodecanethioate'>8Q1</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NFS1, NIFS, HUSSY-08 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), LYRM4, C6orf149, ISD11, CGI-203 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), acpP, DQL48_09575, EOL36_14065 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ISCU, NIFUN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), FXN, FRDA, X25 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8Q1:S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl]+dodecanethioate'>8Q1</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cysteine_desulfurase Cysteine desulfurase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.8.1.7 2.8.1.7] </span></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=6nzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzu OCA], [https://pdbe.org/6nzu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nzu RCSB], [https://www.ebi.ac.uk/pdbsum/6nzu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzu 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=6nzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzu OCA], [http://pdbe.org/6nzu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nzu RCSB], [http://www.ebi.ac.uk/pdbsum/6nzu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ISCU_HUMAN ISCU_HUMAN]] Hereditary myopathy with lactic acidosis due to ISCU deficiency. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/NFS1_HUMAN NFS1_HUMAN]] Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. [[http://www.uniprot.org/uniprot/LYRM4_HUMAN LYRM4_HUMAN]] Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/FRDA_HUMAN FRDA_HUMAN]] Defects in FXN are the cause of Friedreich ataxia (FRDA) [MIM:[http://omim.org/entry/229300 229300]]. FRDA is an autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region.[:][:]<ref>PMID:9150176</ref> <ref>PMID:9779809</ref> <ref>PMID:10732799</ref> <ref>PMID:9989622</ref> [:]<ref>PMID:10874325</ref> <ref>PMID:19629184</ref> | + | [https://www.uniprot.org/uniprot/NFS1_HUMAN NFS1_HUMAN] Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ISCU_HUMAN ISCU_HUMAN]] Scaffold protein for the de novo synthesis of iron-sulfur (Fe-S) clusters within mitochondria, which is required for maturation of both mitochondrial and cytoplasmic [2Fe-2S] and [4Fe-4S] proteins (PubMed:11060020). First, a [2Fe-2S] cluster is transiently assembled on the scaffold protein ISCU. In a second step, the cluster is released from ISCU, transferred to a glutaredoxin GLRX5, followed by the formation of mitochondrial [2Fe-2S] proteins, the synthesis of [4Fe-4S] clusters and their target-specific insertion into the recipient apoproteins. Cluster assembly on ISCU depends on the function of the cysteine desulfurase complex NFS1-LYRM4/ISD11, which serves as the sulfur donor for cluster synthesis, the iron-binding protein frataxin as the putative iron donor, and the electron transfer chain comprised of ferredoxin reductase and ferredoxin, which receive their electrons from NADH (By similarity).[UniProtKB:Q03020]<ref>PMID:11060020</ref> [[http://www.uniprot.org/uniprot/NFS1_HUMAN NFS1_HUMAN]] Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron-sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor.<ref>PMID:18650437</ref> [[http://www.uniprot.org/uniprot/A0A437HBF4_ECOLX A0A437HBF4_ECOLX]] Carrier of the growing fatty acid chain in fatty acid biosynthesis.[HAMAP-Rule:MF_01217][RuleBase:RU003545][SAAS:SAAS00380737] [[http://www.uniprot.org/uniprot/LYRM4_HUMAN LYRM4_HUMAN]] Required for nuclear and mitochondrial iron-sulfur protein biosynthesis.<ref>PMID:17331979</ref> <ref>PMID:19454487</ref> [[http://www.uniprot.org/uniprot/FRDA_HUMAN FRDA_HUMAN]] Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1.<ref>PMID:20053667</ref> <ref>PMID:11823441</ref> <ref>PMID:12755598</ref> <ref>PMID:12785837</ref> <ref>PMID:15123683</ref> <ref>PMID:15247478</ref> <ref>PMID:15641778</ref> <ref>PMID:16239244</ref> <ref>PMID:16608849</ref> | + | [https://www.uniprot.org/uniprot/NFS1_HUMAN NFS1_HUMAN] Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron-sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor.<ref>PMID:18650437</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| | + | *[[Acyl carrier protein 3D structures|Acyl carrier protein 3D structures]] |
| | *[[Cysteine desulfurase 3D structures|Cysteine desulfurase 3D structures]] | | *[[Cysteine desulfurase 3D structures|Cysteine desulfurase 3D structures]] |
| | *[[Frataxin 3D Structures|Frataxin 3D Structures]] | | *[[Frataxin 3D Structures|Frataxin 3D Structures]] |
| Line 30: |
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| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Cysteine desulfurase]] | + | [[Category: Escherichia coli]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Alain, M]] | + | [[Category: Alain M]] |
| - | [[Category: Christine, B]] | + | [[Category: Christine B]] |
| - | [[Category: Claire, S D]] | + | [[Category: Claire SD]] |
| - | [[Category: Fox, N G]] | + | [[Category: Fox NG]] |
| - | [[Category: Han, S]] | + | [[Category: Han S]] |
| - | [[Category: Joseph, N]] | + | [[Category: Joseph N]] |
| - | [[Category: Xidong, F]] | + | [[Category: Xidong F]] |
| - | [[Category: Yu, X]] | + | [[Category: Yu X]] |
| - | [[Category: Yue, W W]] | + | [[Category: Yue WW]] |
| - | [[Category: Human frataxin-bound iron-sulfur cluster assembly complex]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
NFS1_HUMAN Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency.
Function
NFS1_HUMAN Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron-sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor.[1]
Publication Abstract from PubMed
The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich's ataxia (FRDA). Here the 3.2 A resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.,Fox NG, Yu X, Feng X, Bailey HJ, Martelli A, Nabhan JF, Strain-Damerell C, Bulawa C, Yue WW, Han S Nat Commun. 2019 May 17;10(1):2210. doi: 10.1038/s41467-019-09989-y. PMID:31101807[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Marelja Z, Stocklein W, Nimtz M, Leimkuhler S. A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J Biol Chem. 2008 Sep 12;283(37):25178-85. doi: 10.1074/jbc.M804064200. Epub 2008, Jul 23. PMID:18650437 doi:http://dx.doi.org/10.1074/jbc.M804064200
- ↑ Fox NG, Yu X, Feng X, Bailey HJ, Martelli A, Nabhan JF, Strain-Damerell C, Bulawa C, Yue WW, Han S. Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. Nat Commun. 2019 May 17;10(1):2210. doi: 10.1038/s41467-019-09989-y. PMID:31101807 doi:http://dx.doi.org/10.1038/s41467-019-09989-y
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