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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 50 6478-87 (2011)
Related entries: 3s4m, 3s5e, 3s5f

Cited: 30 times
EuropePMC logo PMID: 21671584

Abstract

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 that Fxn facilitates 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.

Articles - 3s5d mentioned but not cited (2)

  1. Trinucleotide repeats: a structural perspective. Almeida B, Fernandes S, Abreu IA, Macedo-Ribeiro S. Front Neurol 4 76 (2013)
  2. 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 50 6478-6487 (2011)


Reviews citing this publication (5)

  1. Emerging critical roles of Fe-S clusters in DNA replication and repair. Fuss JO, Tsai CL, Ishida JP, Tainer JA. Biochim Biophys Acta 1853 1253-1271 (2015)
  2. Coming into view: eukaryotic iron chaperones and intracellular iron delivery. Philpott CC. J Biol Chem 287 13518-13523 (2012)
  3. Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models. Martelli A, Napierala M, Puccio H. Dis Model Mech 5 165-176 (2012)
  4. Impact of Drosophila Models in the Study and Treatment of Friedreich's Ataxia. Monnier V, Llorens JV, Navarro JA. Int J Mol Sci 19 E1989 (2018)
  5. Molecular Details of the Frataxin-Scaffold Interaction during Mitochondrial Fe-S Cluster Assembly. Campbell CJ, Pall AE, Naik AR, Thompson LN, Stemmler TL. Int J Mol Sci 22 6006 (2021)

Articles citing this publication (23)

  1. Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry. Bridwell-Rabb J, Fox NG, Tsai CL, Winn AM, Barondeau DP. Biochemistry 53 4904-4913 (2014)
  2. Effector role reversal during evolution: the case of frataxin in Fe-S cluster biosynthesis. Bridwell-Rabb J, Iannuzzi C, Pastore A, Barondeau DP. Biochemistry 51 2506-2514 (2012)
  3. 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 10 2210 (2019)
  4. Structure-function analysis of Friedreich's ataxia mutants reveals determinants of frataxin binding and activation of the Fe-S assembly complex. Bridwell-Rabb J, Winn AM, Barondeau DP. Biochemistry 50 7265-7274 (2011)
  5. Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration. Chen K, Lin G, Haelterman NA, Ho TS, Li T, Li Z, Duraine L, Graham BH, Jaiswal M, Yamamoto S, Rasband MN, Bellen HJ. Elife 5 e16043 (2016)
  6. Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex. Fox NG, Das D, Chakrabarti M, Lindahl PA, Barondeau DP. Biochemistry 54 3880-3889 (2015)
  7. Frataxin levels in peripheral tissue in Friedreich ataxia. Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR. Ann Clin Transl Neurol 2 831-842 (2015)
  8. Mechanism of activation of the human cysteine desulfurase complex by frataxin. Patra S, Barondeau DP. Proc Natl Acad Sci U S A 116 19421-19430 (2019)
  9. Overlapping binding sites of the frataxin homologue assembly factor and the heat shock protein 70 transfer factor on the Isu iron-sulfur cluster scaffold protein. Manicki M, Majewska J, Ciesielski S, Schilke B, Blenska A, Kominek J, Marszalek J, Craig EA, Dutkiewicz R. J Biol Chem 289 30268-30278 (2014)
  10. Mitochondrial Cysteine Desulfurase and ISD11 Coexpressed in Escherichia coli Yield Complex Containing Acyl Carrier Protein. Cai K, Frederick RO, Tonelli M, Markley JL. ACS Chem Biol 12 918-921 (2017)
  11. Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms. Li H, Gakh O, Smith DY, Ranatunga WK, Isaya G. J Biol Chem 288 4116-4127 (2013)
  12. Selected missense mutations impair frataxin processing in Friedreich ataxia. Clark E, Butler JS, Isaacs CJ, Napierala M, Lynch DR. Ann Clin Transl Neurol 4 575-584 (2017)
  13. Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery. Gakh O, Ranatunga W, Smith DY, Ahlgren EC, Al-Karadaghi S, Thompson JR, Isaya G. J Biol Chem 291 21296-21321 (2016)
  14. CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment. Scaini MC, Minervini G, Elefanti L, Ghiorzo P, Pastorino L, Tognazzo S, Agata S, Quaggio M, Zullato D, Bianchi-Scarrà G, Montagna M, D'Andrea E, Menin C, Tosatto SC. Hum Mutat 35 828-840 (2014)
  15. Human Frataxin Folds Via an Intermediate State. Role of the C-Terminal Region. Faraj SE, González-Lebrero RM, Roman EA, Santos J. Sci Rep 6 20782 (2016)
  16. Mechanism of frataxin "bypass" in human iron-sulfur cluster biosynthesis with implications for Friedreich's ataxia. Das D, Patra S, Bridwell-Rabb J, Barondeau DP. J Biol Chem 294 9276-9284 (2019)
  17. The alteration of the C-terminal region of human frataxin distorts its structural dynamics and function. Faraj SE, Roman EA, Aran M, Gallo M, Santos J. FEBS J 281 3397-3419 (2014)
  18. A dynamic model of the proteins that form the initial iron-sulfur cluster biogenesis machinery in yeast mitochondria. Amela I, Delicado P, Gómez A, Querol E, Cedano J. Protein J 32 183-196 (2013)
  19. Robust Production, Crystallization, Structure Determination, and Analysis of [Fe-S] Proteins: Uncovering Control of Electron Shuttling and Gating in the Respiratory Metabolism of Molybdopterin Guanine Dinucleotide Enzymes. Tsai CL, Tainer JA. Methods Enzymol 599 157-196 (2018)
  20. A helix-coil transition induced by the metal ion interaction with a grafted iron-binding site of the CyaY protein family. Vazquez DS, Agudelo WA, Yone A, Vizioli N, Arán M, González Flecha FL, González Lebrero MC, Santos J. Dalton Trans 44 2370-2379 (2015)
  21. Biophysical characterisation of the recombinant human frataxin precursor. Castro IH, Ferrari A, Herrera MG, Noguera ME, Maso L, Benini M, Rufini A, Testi R, Costantini P, Santos J. FEBS Open Bio 8 390-405 (2018)
  22. Identification of a novel missense mutation in Friedreich's ataxia -FXNW 168R. Clark E, Strawser C, Schadt K, Lynch DR. Ann Clin Transl Neurol 6 812-816 (2019)
  23. Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations. Medina-Carbonero M, Sanz-Alcázar A, Britti E, Delaspre F, Cabiscol E, Ros J, Tamarit J. Cell Mol Life Sci 79 74 (2022)


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