Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering

Christopher A G Söderberg, Alexander V. Shkumatov, Sreekanth Rajan, Oleksandr Gakh, Dmitri I. Svergun, Grazia Isaya, Salam Al-Karadaghi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Frataxin is a mitochondrial protein with a central role in iron homeostasis. Defects in frataxin function lead to Friedreich's ataxia, a progressive neurodegenerative disease with childhood onset. The function of frataxin has been shown to be closely associated with its ability to form oligomeric species; however, the factors controlling oligomerization and the types of oligomers present in solution are a matter of debate. Using small-angle X-ray scattering, we found that Co 2+, glycerol, and a single amino acid substitution at the N-terminus, Y73A, facilitate oligomerization of yeast frataxin, resulting in a dynamic equilibrium between monomers, dimers, trimers, hexamers, and higher-order oligomers. Using X-ray crystallography, we found that Co 2+ binds inside the channel at the 3-fold axis of the trimer, which suggests that the metal has an oligomer-stabilizing role. The results reveal the types of oligomers present in solution and support our earlier suggestions that the trimer is the main building block of yeast frataxin oligomers. They also indicate that different mechanisms may control oligomer stability and oligomerization in vivo.

Original languageEnglish (US)
Pages (from-to)783-797
Number of pages15
JournalJournal of Molecular Biology
Volume414
Issue number5
DOIs
StatePublished - Dec 16 2011

Fingerprint

X Ray Crystallography
Yeasts
X-Rays
Friedreich Ataxia
Mitochondrial Proteins
Amino Acid Substitution
Neurodegenerative Diseases
Glycerol
Homeostasis
Iron
Metals
frataxin

Keywords

  • Friedreich's ataxia
  • metal chaperone
  • neurodegenerative diseases
  • protein flexibility
  • protein oligomerization

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Söderberg, C. A. G., Shkumatov, A. V., Rajan, S., Gakh, O., Svergun, D. I., Isaya, G., & Al-Karadaghi, S. (2011). Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering. Journal of Molecular Biology, 414(5), 783-797. https://doi.org/10.1016/j.jmb.2011.10.034

Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering. / Söderberg, Christopher A G; Shkumatov, Alexander V.; Rajan, Sreekanth; Gakh, Oleksandr; Svergun, Dmitri I.; Isaya, Grazia; Al-Karadaghi, Salam.

In: Journal of Molecular Biology, Vol. 414, No. 5, 16.12.2011, p. 783-797.

Research output: Contribution to journalArticle

Söderberg, CAG, Shkumatov, AV, Rajan, S, Gakh, O, Svergun, DI, Isaya, G & Al-Karadaghi, S 2011, 'Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering', Journal of Molecular Biology, vol. 414, no. 5, pp. 783-797. https://doi.org/10.1016/j.jmb.2011.10.034
Söderberg, Christopher A G ; Shkumatov, Alexander V. ; Rajan, Sreekanth ; Gakh, Oleksandr ; Svergun, Dmitri I. ; Isaya, Grazia ; Al-Karadaghi, Salam. / Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering. In: Journal of Molecular Biology. 2011 ; Vol. 414, No. 5. pp. 783-797.
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