The Molecular Basis of Iron-induced Oligomerization of Frataxin and the Role of the Ferroxidation Reaction in Oligomerization

The role of the mitochondrial protein frataxin in iron storage and detoxification, iron delivery to iron-sulfur cluster biosynthesis, heme biosynthesis, and aconitase repair has been extensively studied during the last decade. However, still no general consensus exists on the details of the mechanis...

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Published in:	The Journal of biological chemistry 2013-03, Vol.288 (12), p.8156-8167
Main Authors:	Söderberg, Christopher A.G., Rajan, Sreekanth, Shkumatov, Alexander V., Gakh, Oleksandr, Schaefer, Susanne, Ahlgren, Eva-Christina, Svergun, Dmitri I., Isaya, Grazia, Al-Karadaghi, Salam
Format:	Article
Language:	eng
Subjects:	Amino Acid Sequence Amino Acid Substitution Binding Sites Biologi Biological Sciences Conserved Sequence Crystal Structure Crystallography, X-Ray Escherichia coli Proteins - chemistry Frataxin Iron Iron - chemistry Iron Metabolism Iron-Binding Proteins - chemistry Iron-Binding Proteins - genetics Metalloproteins Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Natural Sciences Naturvetenskap Oligomerization Oxidation-Reduction Protein Binding Protein Interaction Domains and Motifs Protein Multimerization Protein Structure Protein Structure and Folding Protein Structure, Quaternary Protein Structure, Secondary Protein-Protein Interactions SAXS Scattering, Small Angle Thermodynamics
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Summary:	The role of the mitochondrial protein frataxin in iron storage and detoxification, iron delivery to iron-sulfur cluster biosynthesis, heme biosynthesis, and aconitase repair has been extensively studied during the last decade. However, still no general consensus exists on the details of the mechanism of frataxin function and oligomerization. Here, using small-angle x-ray scattering and x-ray crystallography, we describe the solution structure of the oligomers formed during the iron-dependent assembly of yeast (Yfh1) and Escherichia coli (CyaY) frataxin. At an iron-to-protein ratio of 2, the initially monomeric Yfh1 is converted to a trimeric form in solution. The trimer in turn serves as the assembly unit for higher order oligomers induced at higher iron-to-protein ratios. The x-ray crystallographic structure obtained from iron-soaked crystals demonstrates that iron binds at the trimer-trimer interaction sites, presumably contributing to oligomer stabilization. For the ferroxidation-deficient D79A/D82A variant of Yfh1, iron-dependent oligomerization may still take place, although >50% of the protein is found in the monomeric state at the highest iron-to-protein ratio used. This demonstrates that the ferroxidation reaction controls frataxin assembly and presumably the iron chaperone function of frataxin and its interactions with target proteins. For E. coli CyaY, the assembly unit of higher order oligomers is a tetramer, which could be an effect of the much shorter N-terminal region of this protein. The results show that understanding of the mechanistic features of frataxin function requires detailed knowledge of the interplay between the ferroxidation reaction, iron-induced oligomerization, and the structure of oligomers formed during assembly. Background: Iron-induced oligomerization of frataxin is still poorly understood. Results: The molecular basis of iron-induced oligomerization of yeast and bacterial frataxin is revealed. Catalyzed ferroxidation is required for correct oligomerization of Yfh1. Conclusion: Frataxin forms different oligomeric species at physiological conditions. Significance: Iron availability controls frataxin oligomerization, which in turn may control the processes that require iron delivery by frataxin.
ISSN:	0021-9258 1083-351X 1083-351X