6nzu

Structural highlights

Disease

[ISCU_HUMAN] Hereditary myopathy with lactic acidosis due to ISCU deficiency. The disease is caused by mutations affecting the gene represented in this entry. [NFS1_HUMAN] Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. [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. [FRDA_HUMAN] Defects in FXN are the cause of Friedreich ataxia (FRDA) [MIM: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.[:][:]^{[1] [2] [3] [4]} [:]^{[5] [6]}

Function

[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]^[7] [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.^[8] [LYRM4_HUMAN] Required for nuclear and mitochondrial iron-sulfur protein biosynthesis.^{[9] [10]} [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.^{[11] [12] [13] [14] [15] [16] [17] [18] [19]}

References

1. ↑ Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997 May;60(5):1251-6. PMID:9150176
2. ↑ Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies. Am J Med Genet. 1998 Oct 12;79(5):396-9. PMID:9779809
3. ↑ Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, Yeung L, Nassif N, Nicholson GA. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998 Aug;1(4):253-7. PMID:10732799
4. ↑ Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson KH, Kohlschutter A, Muller U, Mandel JL, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M. Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999 Feb;45(2):200-6. PMID:9989622
5. ↑ Al-Mahdawi S, Pook M, Chamberlain S. A novel missense mutation (L198R) in the Friedreich's ataxia gene. Hum Mutat. 2000 Jul;16(1):95. PMID:10874325 doi:<95::AID-HUMU29>3.0.CO;2-E 10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E
6. ↑ Calmels N, Schmucker S, Wattenhofer-Donze M, Martelli A, Vaucamps N, Reutenauer L, Messaddeq N, Bouton C, Koenig M, Puccio H. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia. PLoS One. 2009 Jul 24;4(7):e6379. PMID:19629184 doi:10.1371/journal.pone.0006379
7. ↑ Tong WH, Rouault T. Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. EMBO J. 2000 Nov 1;19(21):5692-700. PMID:11060020 doi:http://dx.doi.org/10.1093/emboj/19.21.5692
8. ↑ 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
9. ↑ Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007 Apr 15;16(8):929-41. Epub 2007 Mar 1. PMID:17331979 doi:http://dx.doi.org/ddm038
10. ↑ Shi Y, Ghosh MC, Tong WH, Rouault TA. Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis. Hum Mol Genet. 2009 Aug 15;18(16):3014-25. doi: 10.1093/hmg/ddp239. Epub 2009 May, 18. PMID:19454487 doi:http://dx.doi.org/10.1093/hmg/ddp239
11. ↑ Condo I, Malisan F, Guccini I, Serio D, Rufini A, Testi R. Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin. Hum Mol Genet. 2010 Jan 20. PMID:20053667 doi:ddp592
12. ↑ Cavadini P, O'Neill HA, Benada O, Isaya G. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002 Feb 1;11(3):217-27. PMID:11823441
13. ↑ Nichol H, Gakh O, O'Neill HA, Pickering IJ, Isaya G, George GN. Structure of frataxin iron cores: an X-ray absorption spectroscopic study. Biochemistry. 2003 May 27;42(20):5971-6. PMID:12755598 doi:10.1021/bi027021l
14. ↑ Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc. 2003 May 21;125(20):6078-84. PMID:12785837 doi:10.1021/ja027967i
15. ↑ Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004 Jun 18;279(25):25943-6. Epub 2004 Apr 27. PMID:15123683 doi:10.1074/jbc.C400107200
16. ↑ Bulteau AL, O'Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004 Jul 9;305(5681):242-5. PMID:15247478 doi:10.1126/science.1098991
17. ↑ O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, Ferreira GC, Isaya G. Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry. 2005 Jan 18;44(2):537-45. PMID:15641778 doi:10.1021/bi048459j
18. ↑ Schoenfeld RA, Napoli E, Wong A, Zhan S, Reutenauer L, Morin D, Buckpitt AR, Taroni F, Lonnerdal B, Ristow M, Puccio H, Cortopassi GA. Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet. 2005 Dec 15;14(24):3787-99. Epub 2005 Oct 20. PMID:16239244 doi:10.1093/hmg/ddi393
19. ↑ Condo I, Ventura N, Malisan F, Tomassini B, Testi R. A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem. 2006 Jun 16;281(24):16750-6. Epub 2006 Apr 11. PMID:16608849 doi:M511960200