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3s4m, resolution 1.30Å ()
Gene: FRDA, FXN, X25 (Homo sapiens)
Activity: Ferroxidase, with EC number
Related: 3s5d, 3s5e, 3s5f

Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Crystal structure of wild-type human frataxin

Publication Abstract from PubMed

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that has been linked to defects in the protein frataxin (Fxn). Most FRDA patients have a GAA expansion in the first intron of their Fxn gene that decreases protein expression. Some FRDA patients have a GAA expansion on one allele and a missense mutation on the other allele. Few functional details are known for the ~15 different missense mutations identified in FRDA patients. Here in vitro evidence is presented that indicates the FRDA I154F and W155R variants bind more weakly to the complex of Nfs1, Isd11, and Isu2 and thereby are defective in forming the four-component SDUF complex that constitutes the core of the Fe-S cluster assembly machine. The binding affinities follow the trend Fxn ~ I154F > W155F > W155A ~ W155R. The Fxn variants also have diminished ability to function as part of the SDUF complex to stimulate the cysteine desulfurase reaction and facilitate Fe-S cluster assembly. Four crystal structures, including the first for a FRDA variant, reveal specific rearrangements associated with the loss of function and lead to a model for Fxn-based activation of the Fe-S cluster assembly complex. Importantly, the weaker binding and lower activity for FRDA variants correlate with the severity of disease progression. Together, these results suggest Fxn triggers sulfur transfer from Nfs1 to Isu2, and that these in vitro assays are sensitive and appropriate for deciphering functional defects and mechanistic details for human Fe-S cluster biosynthesis.

Friedreich's ataxia variants I154F and W155R diminish frataxin-based activation of the iron-sulfur cluster assembly complex., Tsai CL, Bridwell-Rabb J, Barondeau DP, Biochemistry. 2011 Jun 14. PMID:21671584

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.


[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]


[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.[7][8][9][10][11][12][13][14][15]

About this Structure

3s4m is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.


  • Tsai CL, Bridwell-Rabb J, Barondeau DP. Friedreich's ataxia variants I154F and W155R diminish frataxin-based activation of the iron-sulfur cluster assembly complex. Biochemistry. 2011 Jun 14. PMID:21671584 doi:10.1021/bi200666h
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  13. 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
  14. 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
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