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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
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 93)

Abstract

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.

Keywords

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

Abbreviations

4’PPT

4’-phosphopantetheine

ACP

Acyl carrier protein

AFM

Atomic Force Microscopy

CD

Circular dichroism

CPMG

The Carr-Purcell-Meiboom-Gill pulse sequence

CTR

C-terminal region

CyaY

Frataxin from E. coli

DLS

Dynamic light scattering

DOSY

Diffusion order spectroscopy

EM

Electron microscopy

FDX

Ferredoxin

Fe–S

Iron–sulfur

FRDA

Friedreich’s Ataxia

FXN

Frataxin

HPLC

High-performance liquid chromatography

HSQC

Heteronuclear single quantum coherence spectroscopy

ISCU

Iron–sulfur cluster assembly enzyme

ISD11

NFS1 interacting protein

ITC

Isothermal titration calorimetry

NFS1

Mitochondrial desulfurase enzyme

NMR

Nuclear magnetic resonance

NOE

Nuclear Overhauser effect

PAGE

Polyacrylamide gel electrophoresis

PDB

Protein Data Bank

RMSD

Root-mean-square deviation

SAXS

Small-angle X-ray scattering

SDS

Sodium dodecyl sulfate

SEC

Size exclusion chromatography

SUF

Sulfur assimilation

Notes

Acknowledgements

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.

Notes

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).

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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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