Frataxin Structure and Function

  • Ignacio Hugo Castro
  • María Florencia Pignataro
  • Karl Ellioth Sewell
  • Lucía Daniela Espeche
  • María Georgina Herrera
  • Martín Ezequiel Noguera
  • Liliana Dain
  • Alejandro Daniel Nadra
  • Martín Aran
  • Clara Smal
  • Mariana Gallo
  • Javier SantosEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 93)


Mammalian frataxin is a small mitochondrial protein involved in iron sulfur cluster assembly. Frataxin deficiency causes the neurodegenerative disease Friedreich’s Ataxia. Valuable knowledge has been gained on the structural dynamics of frataxin, metal-ion-protein interactions, as well as on the effect of mutations on protein conformation, stability and internal motions. Additionally, laborious studies concerning the enzymatic reactions involved have allowed for understanding the capability of frataxin to modulate Fe–S cluster assembly function. Remarkably, frataxin biological function depends on its interaction with some proteins to form a supercomplex, among them NFS1 desulfurase and ISCU, the scaffolding protein. By combining multiple experimental tools including high resolution techniques like NMR and X-ray, but also SAXS, crosslinking and mass-spectrometry, it was possible to build a reliable model of the structure of the desulfurase supercomplex NFS1/ACP-ISD11/ISCU/frataxin. In this chapter, we explore these issues showing how the scientific view concerning frataxin structure-function relationships has evolved over the last years.


Frataxin Structural dynamics Structure-Function relationships Iron binding Iron–Sulfur cluster assembly Conformational stability 





Acyl carrier protein


Atomic Force Microscopy


Circular dichroism


The Carr-Purcell-Meiboom-Gill pulse sequence


C-terminal region


Frataxin from E. coli


Dynamic light scattering


Diffusion order spectroscopy


Electron microscopy






Friedreich’s Ataxia




High-performance liquid chromatography


Heteronuclear single quantum coherence spectroscopy


Iron–sulfur cluster assembly enzyme


NFS1 interacting protein


Isothermal titration calorimetry


Mitochondrial desulfurase enzyme


Nuclear magnetic resonance


Nuclear Overhauser effect


Polyacrylamide gel electrophoresis


Protein Data Bank


Root-mean-square deviation


Small-angle X-ray scattering


Sodium dodecyl sulfate


Size exclusion chromatography


Sulfur assimilation



This work was supported by the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT PICT2016-2280), the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), the Universidad de Buenos Aires and FARA, Friedreich’s Ataxia Research Alliance.


The authors declare no competing financial interest. While this chapter was being edited, Fox and et al. presented a cryo-electron microscopy structure (3.2 Å resolution, PDB ID: 6NZU) of the human frataxin-bound iron-sulfur cluster assembly complex, containing two copies of the NFS1/ISD11-ACP/ISCU/FXN hetero-pentamer. A key feature of FXN binding is its simultaneous interactions with both NFS1 protomers of the complex and with ISCU (Fox et al. 2019).


  1. Adamec J, Rusnak F, Owen WG, Naylor S, Benson LM, Gacy AM, Isaya G (2000) Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am J Hum Genet 67(3):549–562CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adinolfi S, Iannuzzi C, Prischi F, Pastore C, Iametti S, Martin SR, Bonomi F, Pastore A (2009) Bacterial frataxin CyaY is the gatekeeper of iron–sulfur cluster formation catalyzed by IscS. Nat Struct Mol Biol 16(4):390–396CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adinolfi S, Puglisi R, Crack JC, Iannuzzi C, Dal Piaz F, Konarev PV, Svergun DI, Martin S, Le Brun NE, Pastore A (2017) The MOLECULAR bases of the dual regulation of bacterial iron sulfur cluster biogenesis by CyaY and IscX. Front Mol Biosci 4:97CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ahlgren EC, Fekry M, Wiemann M, Soderberg CA, Bernfur K, Gakh O, Rasmussen M, Hojrup P, Emanuelsson C, Isaya G, Al-Karadaghi S (2017) Iron-induced oligomerization of human FXN81-210 and bacterial CyaY frataxin and the effect of iron chelators. PLoS ONE 12(12):e0188937CrossRefPubMedPubMedCentralGoogle Scholar
  5. Armas AM, Balparda M, Terenzi A, Busi MV, Pagani MA, Gomez-Casati DF (2019) Ferrochelatase activity of plant frataxin. Biochimie 156:118–122CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bedekovics T, Gajdos GB, Kispal G, Isaya G (2007) Partial conservation of functions between eukaryotic frataxin and the Escherichia coli frataxin homolog CyaY. FEMS Yeast Res 7(8):1276–1284CrossRefPubMedPubMedCentralGoogle Scholar
  7. Benini M, Fortuni S, Condo I, Alfedi G, Malisan F, Toschi N, Serio D, Massaro DS, Arcuri G, Testi R, Rufini A (2017) E3 Ligase RNF126 Directly ubiquitinates frataxin, promoting its degradation: identification of a potential therapeutic target for Friedreich ataxia. Cell Rep 18(8):2007–2017CrossRefPubMedPubMedCentralGoogle Scholar
  8. Boniecki MT, Freibert SA, Muhlenhoff U, Lill R, Cygler M (2017) Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. Nat Commun 8(1):1287CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bridwell-Rabb J, Fox NG, Tsai CL, Winn AM, Barondeau DP (2014) Human frataxin activates Fe–S cluster biosynthesis by facilitating sulfur transfer chemistry. Biochemistry 53(30):4904–4913CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bridwell-Rabb J, Iannuzzi C, Pastore A, Barondeau DP (2012) Effector role reversal during evolution: the case of frataxin in Fe–S cluster biosynthesis. Biochemistry 51(12):2506–2514CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bridwell-Rabb J, Winn AM, Barondeau DP (2011) Structure-function analysis of Friedreich’s ataxia mutants reveals determinants of frataxin binding and activation of the Fe–S assembly complex. Biochemistry 50(33):7265–7274CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cai K, Frederick RO, Dashti H, Markley JL (2018a) Architectural features of human mitochondrial cysteine desulfurase complexes from crosslinking mass spectrometry and small-angle X-ray scattering. Structure 26(8):1127–1136 e 1124Google Scholar
  13. Cai K, Frederick RO, Kim JH, Reinen NM, Tonelli M, Markley JL (2013) Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron–sulfur cluster scaffold protein (ISCU). J Biol Chem 288(40):28755–28770CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cai K, Frederick RO, Tonelli M, Markley JL (2018b) Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe–S cluster assembly. J Inorg Biochem 183:107–116CrossRefPubMedPubMedCentralGoogle Scholar
  15. Cai K, Tonelli M, Frederick RO, Markley JL (2017) Human mitochondrial ferredoxin 1 (FDX1) and ferredoxin 2 (FDX2) both bind cysteine desulfurase and donate electrons for iron–sulfur cluster biosynthesis. Biochemistry 56(3):487–499CrossRefPubMedPubMedCentralGoogle Scholar
  16. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271(5254):1423–1427CrossRefPubMedPubMedCentralGoogle Scholar
  17. Castro IH, Ferrari A, Herrera MG, Noguera ME, Maso L, Benini M, Rufini A, Testi R, Costantini P, Santos J (2018) Biophysical characterisation of the recombinant human frataxin precursor. FEBS Open Bio 8(3):390–405CrossRefPubMedPubMedCentralGoogle Scholar
  18. Cavadini P, Adamec J, Taroni F, Gakh O, Isaya G (2000a) Two-step processing of human frataxin by mitochondrial processing peptidase. Precursor and intermediate forms are cleaved at different rates. J Biol Chem 275(52):41469–41475Google Scholar
  19. Cavadini P, Gellera C, Patel PI, Isaya G (2000b) Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum Mol Genet 9(17):2523–2530CrossRefPubMedPubMedCentralGoogle Scholar
  20. Chamberlain S, Shaw J, Rowland A, Wallis J, South S, Nakamura Y, von Gabain A, Farrall M, Williamson R (1988) Mapping of mutation causing Friedreich’s ataxia to human chromosome 9. Nature 334(6179):248–250CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chamberlain S, Shaw J, Wallis J, Rowland A, Chow L, Farrall M, Keats B, Richter A, Roy M, Melancon S et al (1989) Genetic homogeneity at the Friedreich ataxia locus on chromosome 9. Am J Hum Genet 44(4):518–521PubMedPubMedCentralGoogle Scholar
  22. Chen OS, Hemenway S, Kaplan J (2002) Inhibition of Fe–S cluster biosynthesis decreases mitochondrial iron export: evidence that Yfh1p affects Fe–S cluster synthesis. Proc Natl Acad Sci U S A 99(19):12321–12326CrossRefPubMedPubMedCentralGoogle Scholar
  23. Cherubini F, Serio D, Guccini I, Fortuni S, Arcuri G, Condo I, Rufini A, Moiz S, Camerini S, Crescenzi M, Testi R, Malisan F (2015) Src inhibitors modulate frataxin protein levels. Hum Mol Genet 24(15):4296–4305CrossRefPubMedPubMedCentralGoogle Scholar
  24. Clark E, Butler JS, Isaacs CJ, Napierala M, Lynch DR (2017) Selected missense mutations impair frataxin processing in Friedreich ataxia. Ann Clin Transl Neurol 4(8):575–584CrossRefPubMedPubMedCentralGoogle Scholar
  25. Correia AR, Adinolfi S, Pastore A, Gomes CM (2006) Conformational stability of human frataxin and effect of Friedreich’s ataxia-related mutations on protein folding. Biochem J 398(3):605–611CrossRefPubMedPubMedCentralGoogle Scholar
  26. Correia AR, Pastore C, Adinolfi S, Pastore A, Gomes CM (2008) Dynamics, stability and iron-binding activity of frataxin clinical mutants. FEBS J 275(14):3680–3690CrossRefPubMedPubMedCentralGoogle Scholar
  27. Cory SA, Van Vranken JG, Brignole EJ, Patra S, Winge DR, Drennan CL, Rutter J, Barondeau DP (2017) Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proc Natl Acad Sci U S A 114(27):E5325–E5334CrossRefPubMedPubMedCentralGoogle Scholar
  28. Cupp-Vickery JR, Urbina H, Vickery LE (2003) Crystal structure of IscS, a cysteine desulfurase from Escherichia coli. J Mol Biol 330(5):1049–1059CrossRefPubMedPubMedCentralGoogle Scholar
  29. Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE (2000) Crystal structure of human frataxin. J Biol Chem 275(40):30753–30756CrossRefPubMedPubMedCentralGoogle Scholar
  30. Duby G, Foury F, Ramazzotti A, Herrmann J, Lutz T (2002) A non-essential function for yeast frataxin in iron–sulfur cluster assembly. Hum Mol Genet 11(21):2635–2643CrossRefGoogle Scholar
  31. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (1996) Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med 335(16):1169–1175CrossRefGoogle Scholar
  32. Faggianelli N, Puglisi R, Veneziano L, Romano S, Frontali M, Vannocci T, Fortuni S, Testi R, Pastore A (2015) Analyzing the Effects of a G137V Mutation in the FXN Gene. Front Mol Neurosci 8:66CrossRefPubMedPubMedCentralGoogle Scholar
  33. Faraj SE, Gonzalez-Lebrero RM, Roman EA, Santos J (2016) Human frataxin folds via an intermediate state. Role of the C-terminal region. Sci Rep 6:20782Google Scholar
  34. Faraj SE, Roman EA, Aran M, Gallo M, Santos J (2014) The alteration of the C-terminal region of human frataxin distorts its structural dynamics and function. FEBS J 281(15):3397–3419CrossRefGoogle Scholar
  35. Faraj SE, Venturutti L, Roman EA, Marino-Buslje CB, Mignone A, Tosatto SC, Delfino JM, Santos J (2013) The role of the N-terminal tail for the oligomerization, folding and stability of human frataxin. FEBS Open Bio 3:310–320CrossRefPubMedPubMedCentralGoogle Scholar
  36. Fekry M, Alshokry W, Grela P, Tchorzewski M, Ahlgren EC, Soderberg CA, Gakh O, Isaya G, Al-Karadaghi S (2017) SAXS and stability studies of iron-induced oligomers of bacterial frataxin CyaY. PLoS ONE 12(9):e0184961CrossRefPubMedPubMedCentralGoogle Scholar
  37. Foury F (1999) Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain. FEBS Lett 456(2):281–284CrossRefPubMedPubMedCentralGoogle Scholar
  38. Foury F, Pastore A, Trincal M (2007) Acidic residues of yeast frataxin have an essential role in Fe–S cluster assembly. EMBO Rep 8(2):194–199CrossRefPubMedPubMedCentralGoogle Scholar
  39. Fox NG, Das D, Chakrabarti M, Lindahl PA, Barondeau DP (2015) Frataxin accelerates [2Fe–2S] cluster formation on the human Fe–S assembly complex. Biochemistry 54(25):3880–3889CrossRefPubMedPubMedCentralGoogle Scholar
  40. Fox NG, Yu X, Feng X, Bailey HJ, Martelli A, Nabhan JF, Strain-Damerell C, Bulawa C, Yue WW, Han S (2019) Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. Nat Commun 10(1)Google Scholar
  41. Friemel M, Marelja Z, Li K, Leimkuhler S (2017) The N-terminus of iron–sulfur cluster assembly factor ISD11 Is crucial for subcellular targeting and interaction with l-cysteine desulfurase NFS1. Biochemistry 56(12):1797–1808CrossRefPubMedPubMedCentralGoogle Scholar
  42. Gakh O, Adamec J, Gacy AM, Twesten RD, Owen WG, Isaya G (2002) Physical evidence that yeast frataxin is an iron storage protein. Biochemistry 41(21):6798–6804CrossRefPubMedPubMedCentralGoogle Scholar
  43. Galea CA, Huq A, Lockhart PJ, Tai G, Corben LA, Yiu EM, Gurrin LC, Lynch DR, Gelbard S, Durr A, Pousset F, Parkinson M, Labrum R, Giunti P, Perlman SL, Delatycki MB, Evans-Galea MV (2016) Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia. Ann Neurol 79(3):485–495CrossRefPubMedPubMedCentralGoogle Scholar
  44. Gentry LE, Thacker MA, Doughty R, Timkovich R, Busenlehner LS (2013) His86 from the N-terminus of frataxin coordinates iron and is required for Fe–S cluster synthesis. Biochemistry 52(35):6085–6096CrossRefPubMedPubMedCentralGoogle Scholar
  45. Gerber J, Muhlenhoff U, Lill R (2003) An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep 4(9):906–911CrossRefPubMedPubMedCentralGoogle Scholar
  46. Gomes CM, Santos R (2013) Neurodegeneration in Friedreich’s ataxia: from defective frataxin to oxidative stress. Oxid Med Cell Longev 2013:487534CrossRefPubMedPubMedCentralGoogle Scholar
  47. Guo L, Wang Q, Weng L, Hauser LA, Strawser CJ, Mesaros C, Lynch DR, Blair IA (2018) Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes. Sci Rep 8(1):17043CrossRefPubMedPubMedCentralGoogle Scholar
  48. Herrera MG, Pignataro MF, Noguera ME, Cruz KM, Santos J (2018) Rescuing the rescuer: on the protein complex between the human mitochondrial acyl carrier protein and ISD11. ACS Chem Biol 13(6):1455–1462CrossRefGoogle Scholar
  49. Hidese R, Mihara H, Esaki N (2011) Bacterial cysteine desulfurases: versatile key players in biosynthetic pathways of sulfur-containing biofactors. Appl Microbiol Biotechnol 91(1):47–61CrossRefGoogle Scholar
  50. Huynen MA, Snel B, Bork P, Gibson TJ (2001) The phylogenetic distribution of frataxin indicates a role in iron–sulfur cluster protein assembly. Hum Mol Genet 10(21):2463–2468CrossRefGoogle Scholar
  51. Iannuzzi C, Adinolfi S, Howes BD, Garcia-Serres R, Clemancey M, Latour JM, Smulevich G, Pastore A (2011) The role of CyaY in iron sulfur cluster assembly on the E. coli IscU scaffold protein. PLoS One 6 (7):e21992Google Scholar
  52. Karlberg T, Schagerlof U, Gakh O, Park S, Ryde U, Lindahl M, Leath K, Garman E, Isaya G, Al-Karadaghi S (2006) The structures of frataxin oligomers reveal the mechanism for the delivery and detoxification of iron. Structure 14(10):1535–1546CrossRefPubMedPubMedCentralGoogle Scholar
  53. Kim JH, Frederick RO, Reinen NM, Troupis AT, Markley JL (2013) [2Fe–2S]-ferredoxin binds directly to cysteine desulfurase and supplies an electron for iron–sulfur cluster assembly but is displaced by the scaffold protein or bacterial frataxin. J Am Chem Soc 135(22):8117–8120CrossRefPubMedPubMedCentralGoogle Scholar
  54. Koeppen AH (2013) Nikolaus Friedreich and degenerative atrophy of the dorsal columns of the spinal cord. J Neurochem 126(Suppl 1):4–10CrossRefPubMedPubMedCentralGoogle Scholar
  55. Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M (1997) Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 16(4):345–351CrossRefPubMedPubMedCentralGoogle Scholar
  56. Koutnikova H, Campuzano V, Koenig M (1998) Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. Hum Mol Genet 7(9):1485–1489CrossRefPubMedPubMedCentralGoogle Scholar
  57. Leidgens S, De Smet S, Foury F (2010) Frataxin interacts with Isu1 through a conserved tryptophan in its beta-sheet. Hum Mol Genet 19(2):276–286CrossRefPubMedPubMedCentralGoogle Scholar
  58. Leimkuhler S, Buhning M, Beilschmidt L (2017) Shared sulfur mobilization routes for tRNA Thiolation and molybdenum cofactor biosynthesis in prokaryotes and eukaryotes. Biomolecules 7(1)Google Scholar
  59. Lesuisse E, Santos R, Matzanke BF, Knight SA, Camadro JM, Dancis A (2003) Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum Mol Genet 12(8):879–889CrossRefPubMedPubMedCentralGoogle Scholar
  60. Li DS, Ohshima K, Jiralerspong S, Bojanowski MW, Pandolfo M (1999) Knock-out of the cyaY gene in Escherichia coli does not affect cellular iron content and sensitivity to oxidants. FEBS Lett 456(1):13–16CrossRefPubMedPubMedCentralGoogle Scholar
  61. Maio N, Rouault TA (1853) Iron–sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery. Biochim Biophys Acta 1853(6):1493–1512CrossRefGoogle Scholar
  62. Maliandi MV, Busi MV, Turowski VR, Leaden L, Araya A, Gomez-Casati DF (2011) The mitochondrial protein frataxin is essential for heme biosynthesis in plants. FEBS J 278(3):470–481CrossRefPubMedPubMedCentralGoogle Scholar
  63. Markley JL, Kim JH, Dai Z, Bothe JR, Cai K, Frederick RO, Tonelli M (2013) Metamorphic protein IscU alternates conformations in the course of its role as the scaffold protein for iron–sulfur cluster biosynthesis and delivery. FEBS Lett 587(8):1172–1179CrossRefPubMedPubMedCentralGoogle Scholar
  64. Muhlenhoff U, Gerber J, Richhardt N, Lill R (2003) Components involved in assembly and dislocation of iron–sulfur clusters on the scaffold protein Isu1p. EMBO J 22(18):4815–4825CrossRefPubMedPubMedCentralGoogle Scholar
  65. Noguera ME, Aran M, Smal C, Vazquez DS, Herrera MG, Roman EA, Alaimo N, Gallo M, Santos J (2017) Insights on the conformational dynamics of human frataxin through modifications of loop-1. Arch Biochem Biophys 636:123–137CrossRefPubMedPubMedCentralGoogle Scholar
  66. Noma A, Sakaguchi Y, Suzuki T (2009) Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNA wobble positions. Nucleic Acids Res 37(4):1335–1352CrossRefPubMedPubMedCentralGoogle Scholar
  67. Nuth M, Yoon T, Cowan JA (2002) Iron–sulfur cluster biosynthesis: characterization of iron nucleation sites for assembly of the [2Fe–2S]2 + cluster core in IscU proteins. J Am Chem Soc 124(30):8774–8775CrossRefPubMedPubMedCentralGoogle Scholar
  68. Olsson MH, Sondergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7(2):525–537CrossRefPubMedPubMedCentralGoogle Scholar
  69. Pandey A, Golla R, Yoon H, Dancis A, Pain D (2012) Persulfide formation on mitochondrial cysteine desulfurase: enzyme activation by a eukaryote-specific interacting protein and Fe–S cluster synthesis. Biochem J 448(2):171–187CrossRefPubMedPubMedCentralGoogle Scholar
  70. Pandey A, Gordon DM, Pain J, Stemmler TL, Dancis A, Pain D (2013) Frataxin directly stimulates mitochondrial cysteine desulfurase by exposing substrate-binding sites, and a mutant Fe–S cluster scaffold protein with frataxin-bypassing ability acts similarly. J Biol Chem 288(52):36773–36786CrossRefPubMedPubMedCentralGoogle Scholar
  71. Pandolfo M (2006) Friedreich ataxia: detection of GAA repeat expansions and frataxin point mutations. Methods Mol Med 126:197–216PubMedPubMedCentralGoogle Scholar
  72. Pandolfo M (2009) Friedreich ataxia: the clinical picture. J Neurol 256(Suppl 1):3–8CrossRefPubMedPubMedCentralGoogle Scholar
  73. Parent A, Elduque X, Cornu D, Belot L, Le Caer JP, Grandas A, Toledano MB, D’Autreaux B (2015) Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols. Nat Commun 6:5686CrossRefPubMedPubMedCentralGoogle Scholar
  74. Pastore C, Adinolfi S, Huynen MA, Rybin V, Martin S, Mayer M, Bukau B, Pastore A (2006) YfhJ, a molecular adaptor in iron–sulfur cluster formation or a frataxin-like protein? Structure 14(5):857–867CrossRefPubMedPubMedCentralGoogle Scholar
  75. Patel PI, Isaya G (2001) Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet 69(1):15–24CrossRefPubMedPubMedCentralGoogle Scholar
  76. Popovic M, Sanfelice D, Pastore C, Prischi F, Temussi PA, Pastore A (2015) Selective observation of the disordered import signal of a globular protein by in-cell NMR: the example of frataxins. Protein Sci 24(6):996–1003CrossRefPubMedPubMedCentralGoogle Scholar
  77. Priller J, Scherzer CR, Faber PW, MacDonald ME, Young AB (1997) Frataxin gene of Friedreich’s ataxia is targeted to mitochondria. Ann Neurol 42(2):265–269CrossRefPubMedPubMedCentralGoogle Scholar
  78. Prischi F, Giannini C, Adinolfi S, Pastore A (2009) The N-terminus of mature human frataxin is intrinsically unfolded. FEBS J 276(22):6669–6676CrossRefPubMedPubMedCentralGoogle Scholar
  79. Prischi F, Konarev PV, Iannuzzi C, Pastore C, Adinolfi S, Martin SR, Svergun DI, Pastore A (2010) Structural bases for the interaction of frataxin with the central components of iron–sulphur cluster assembly. Nat Commun 1:95CrossRefPubMedPubMedCentralGoogle Scholar
  80. Ramazzotti A, Vanmansart V, Foury F (2004) Mitochondrial functional interactions between frataxin and Isu1p, the iron–sulfur cluster scaffold protein, in Saccharomyces cerevisiae. FEBS Lett 557(1–3):215–220CrossRefPubMedPubMedCentralGoogle Scholar
  81. Richards TA, van der Giezen M (2006) Evolution of the Isd11-IscS complex reveals a single alpha-proteobacterial endosymbiosis for all eukaryotes. Mol Biol Evol 23(7):1341–1344CrossRefPubMedPubMedCentralGoogle Scholar
  82. Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P (1997) Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia. Nat Genet 17(2):215–217CrossRefPubMedPubMedCentralGoogle Scholar
  83. Rouault TA (2015) Mammalian iron–sulphur proteins: novel insights into biogenesis and function. Nat Rev Mol Cell Biol 16(1):45–55CrossRefPubMedPubMedCentralGoogle Scholar
  84. Rufini A, Cavallo F, Condo I, Fortuni S, De Martino G, Incani O, Di Venere A, Benini M, Massaro DS, Arcuri G, Serio D, Malisan F, Testi R (2015) Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells. Neurobiol Dis 75:91–99CrossRefPubMedPubMedCentralGoogle Scholar
  85. Rufini A, Fortuni S, Arcuri G, Condo I, Serio D, Incani O, Malisan F, Ventura N, Testi R (2011) Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich’s ataxia. Hum Mol Genet 20(7):1253–1261CrossRefPubMedPubMedCentralGoogle Scholar
  86. Sacca F, Marsili A, Puorro G, Antenora A, Pane C, Tessa A, Scoppettuolo P, Nesti C, Brescia Morra V, De Michele G, Santorelli FM, Filla A (2013) Clinical use of frataxin measurement in a patient with a novel deletion in the FXN gene. J Neurol 260(4):1116–1121CrossRefPubMedPubMedCentralGoogle Scholar
  87. Schagerlof U, Elmlund H, Gakh O, Nordlund G, Hebert H, Lindahl M, Isaya G, Al-Karadaghi S (2008) Structural basis of the iron storage function of frataxin from single-particle reconstruction of the iron-loaded oligomer. Biochemistry 47(17):4948–4954CrossRefPubMedPubMedCentralGoogle Scholar
  88. Schmucker S, Argentini M, Carelle-Calmels N, Martelli A, Puccio H (2008) The in vivo mitochondrial two-step maturation of human frataxin. Hum Mol Genet 17(22):3521–3531CrossRefPubMedPubMedCentralGoogle Scholar
  89. Schmucker S, Martelli A, Colin F, Page A, Wattenhofer-Donze M, Reutenauer L, Puccio H (2011) Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron–sulfur assembly complex. PLoS ONE 6(1):e16199CrossRefPubMedPubMedCentralGoogle Scholar
  90. Schoenfeld RA, Napoli E, Wong A, Zhan S, Reutenauer L, Morin D, Buckpitt AR, Taroni F, Lonnerdal B, Ristow M, Puccio H, Cortopassi GA (2005) Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet 14(24):3787–3799CrossRefPubMedPubMedCentralGoogle Scholar
  91. Shi R, Proteau A, Villarroya M, Moukadiri I, Zhang L, Trempe JF, Matte A, Armengod ME, Cygler M (2010) Structural basis for Fe–S cluster assembly and tRNA thiolation mediated by IscS protein-protein interactions. PLoS Biol 8(4):e1000354CrossRefPubMedPubMedCentralGoogle Scholar
  92. Soderberg C, Gillam ME, Ahlgren EC, Hunter GA, Gakh O, Isaya G, Ferreira GC, Al-Karadaghi S (2016) The Structure of the Complex between Yeast Frataxin and Ferrochelatase: characterization and pre-steady state reaction of ferrous iron delivery and heme synthesis. J Biol Chem 291(22):11887–11898CrossRefPubMedPubMedCentralGoogle Scholar
  93. Steinkellner H, Singh HN, Muckenthaler MU, Goldenberg H, Moganty RR, Scheiber-Mojdehkar B, Sturm B (2017) No changes in heme synthesis in human Friedreich s ataxia erythroid progenitor cells. Gene 621:5–11CrossRefPubMedPubMedCentralGoogle Scholar
  94. Telot L, Rousseau E, Lesuisse E, Garcia C, Morlet B, Leger T, Camadro JM, Serre V (2018) Quantitative proteomics in Friedreich’s ataxia B-lymphocytes: a valuable approach to decipher the biochemical events responsible for pathogenesis. Biochim Biophys Acta Mol Basis Dis 1864(4 Pt A):997–1009Google Scholar
  95. Tsai CL, Barondeau DP (2010) Human frataxin is an allosteric switch that activates the Fe–S cluster biosynthetic complex. Biochemistry 49(43):9132–9139CrossRefPubMedPubMedCentralGoogle Scholar
  96. Uchida T, Kobayashi N, Muneta S, Ishimori K (2017) The iron chaperone protein CyaY from Vibrio cholerae Is a heme-binding protein. Biochemistry 56(18):2425–2434CrossRefPubMedPubMedCentralGoogle Scholar
  97. Urbina HD, Silberg JJ, Hoff KG, Vickery LE (2001) Transfer of sulfur from IscS to IscU during Fe/S cluster assembly. J Biol Chem 276(48):44521–44526CrossRefPubMedPubMedCentralGoogle Scholar
  98. Vazquez DS, Agudelo WA, Yone A, Vizioli N, Aran M, Gonzalez Flecha FL, Gonzalez Lebrero MC, Santos J (2015) A helix-coil transition induced by the metal ion interaction with a grafted iron-binding site of the CyaY protein family. Dalton Trans 44(5):2370–2379CrossRefPubMedPubMedCentralGoogle Scholar
  99. Vivas E, Skovran E, Downs DM (2006) Salmonella enterica strains lacking the frataxin homolog CyaY show defects in Fe–S cluster metabolism in vivo. J Bacteriol 188(3):1175–1179CrossRefPubMedPubMedCentralGoogle Scholar
  100. Wachnowsky C, Fidai I, Cowan JA (2018) Iron–sulfur cluster biosynthesis and trafficking—impact on human disease conditions. Metallomics 10(1):9–29CrossRefPubMedPubMedCentralGoogle Scholar
  101. Wang T, Craig EA (2008) Binding of yeast frataxin to the scaffold for Fe–S cluster biogenesis, Isu. J Biol Chem 283(18):12674–12679CrossRefPubMedPubMedCentralGoogle Scholar
  102. Webert H, Freibert SA, Gallo A, Heidenreich T, Linne U, Amlacher S, Hurt E, Muhlenhoff U, Banci L, Lill R (2014) Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin. Nat Commun 5:5013CrossRefPubMedPubMedCentralGoogle Scholar
  103. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G (1999) The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8(3):425–430CrossRefPubMedPubMedCentralGoogle Scholar
  104. Xia H, Cao Y, Dai X, Marelja Z, Zhou D, Mo R, Al-Mahdawi S, Pook MA, Leimkuhler S, Rouault TA, Li K (2012) Novel frataxin isoforms may contribute to the pathological mechanism of Friedreich ataxia. PLoS ONE 7(10):e47847CrossRefPubMedPubMedCentralGoogle Scholar
  105. Yan R, Kelly G, Pastore A (2014) The scaffold protein IscU retains a structured conformation in the Fe–S cluster assembly complex. ChemBioChem 15(11):1682–1686CrossRefPubMedPubMedCentralGoogle Scholar
  106. Yan R, Konarev PV, Iannuzzi C, Adinolfi S, Roche B, Kelly G, Simon L, Martin SR, Py B, Barras F, Svergun DI, Pastore A (2013) Ferredoxin competes with bacterial frataxin in binding to the desulfurase IscS. J Biol Chem 288(34):24777–24787CrossRefPubMedPubMedCentralGoogle Scholar
  107. Yoon H, Golla R, Lesuisse E, Pain J, Donald JE, Lyver ER, Pain D, Dancis A (2012) Mutation in the Fe–S scaffold protein Isu bypasses frataxin deletion. Biochem J 441(1):473–480CrossRefPubMedPubMedCentralGoogle Scholar
  108. Yoon T, Cowan JA (2003) 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 125(20):6078–6084Google Scholar
  109. Yoon T, Cowan JA (2004) Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem 279(25):25943–25946CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ignacio Hugo Castro
    • 1
    • 2
  • María Florencia Pignataro
    • 1
    • 2
  • Karl Ellioth Sewell
    • 1
    • 2
  • Lucía Daniela Espeche
    • 3
  • María Georgina Herrera
    • 1
  • Martín Ezequiel Noguera
    • 1
    • 2
    • 4
  • Liliana Dain
    • 1
    • 3
  • Alejandro Daniel Nadra
    • 1
    • 5
  • Martín Aran
    • 6
  • Clara Smal
    • 6
  • Mariana Gallo
    • 7
  • Javier Santos
    • 1
    • 2
    Email author
  1. 1.Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3)Universidad de Buenos AiresC.A.B.AArgentina
  2. 2.Intituto de Química y Fisicoquímica BiológicasDr. Alejandro Paladini Universidad de Buenos AiresC.A.B.AArgentina
  3. 3.Departamento de Diagnóstico GenéticoCentro Nacional de Genética Médica “Dr. Eduardo E. Castilla”—A.N.L.I.SC.A.B.AArgentina
  4. 4.Departamento de Ciencia y TecnologíaUniversidad Nacional de QuilmesBernalArgentina
  5. 5.Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)Consejo Nacional de Investigaciones Científicas y TécnicasBuenos AiresArgentina
  6. 6.Fundación Instituto Leloir E IIBBA-CONICETBuenos AiresArgentina
  7. 7.IRBM Science Park S.p.APomeziaItaly

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