9.B.21 The Frataxin (Frataxin) Family

The human frataxin protein is a mitochondrial protein, synthesized from a nuclearly encoded precursor, that is probably involved in iron homeostasis. It has been suggested to function in iron transport (Larsson and Luft, 1999). It is encoded by the frdA gene which when defective causes Friedreich's ataxia, an autosomal, recessive, progressive, neurodegenerative disease (Fantini et al. 2017). The disease in most patients is due to GAA triplet repeat expansions in the first intron of the fratixin gene, but sometimes mutation occurs in the coding region. The protein (210 aas) is homologous to the shorter CyaY protein of E. coli (106 aas). The function of this E. coli protein is unknown, but attempts to demonstrate an involvement in iron homeostasis and sensitivity to oxidants using a knockout mutant were not successful (Li et al, 1999).

Frataxin is a ubiquitous protein that plays a role in Fe-S cluster biosynthesis and iron and heme metabolism, although its molecular functions are not clear (Buchensky et al. 2017). In non-photosynthetic eukaryotes, frataxin is encoded by a single gene, and the protein localizes to mitochondria. Buchensky et al. 2017 reported the presence of two functional frataxin isoforms in Zea mays, ZmFH-1 and ZmFH-2. Both proteins have dual localization in mitochondria and chloroplasts, and they play similar but not identical roles in plant cell metabolism. Plant frataxins form dimers and undergo conformational changes under oxygen exposure.  CyaY/frataxin family proteins are among some thirty proteins involved in the synthesis of cellular [2Fe 2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins (Braymer and Lill 2017).

The yeast frataxin homolog, Yfh1, binds two Cu2+ ions and a single Cu+ ion. Mn2+ forms two complexes with Yfh1. Cu and Mn bind Yfh1 with higher affinities than Fe2+(Han et al. 2017).


This family belongs to the .



Braymer, J.J. and R. Lill. (2017). Iron-Sulfur Cluster Biogenesis and Trafficking in Mitochondria. J. Biol. Chem. [Epub: Ahead of Print]

Buchensky, C., M. Sánchez, M. Carrillo, O. Palacios, M. Capdevila, J.M. Domínguez-Vera, M.V. Busi, S. Atrian, M.A. Pagani, and D.F. Gomez-Casati. (2017). Identification of two frataxin isoforms in Zea mays: Structural and functional studies. Biochimie. [Epub: Ahead of Print]

Chiang, S., Z. Kovacevic, S. Sahni, D.J. Lane, A.M. Merlot, D.S. Kalinowski, M.L. Huang, and D.R. Richardson. (2016). Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich''s ataxia. Clin Sci (Lond) 130: 853-870.

Fantini, M., D. Malinverni, P. De Los Rios, and A. Pastore. (2017). New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins Involved in Iron Sulfur Cluster Biogenesis. Front Mol Biosci 4: 40.

Han, T.H.L., J.M. Camadro, R. Santos, E. Lesuisse, J.M. El Hage Chahine, and N.T. Ha-Duong. (2017). Mechanisms of iron and copper-frataxin interactions. Metallomics. [Epub: Ahead of Print]

Karlberg, T., U. Schagerlöf, O. Gakh, S. Park, U. Ryde, M. Lindahl, K. Leath, E. Garman, G. Isaya, and S. Al-Karadaghi. (2006). The structures of frataxin oligomers reveal the mechanism for the delivery and detoxification of iron. Structure 14: 1535-1546.

Larsson N.-G. and R. Luft (1999). Revolution in mitochodrial medicine. FEBS lett. 455: 199-202.

Li, D.S., K. Ohshima, S. Tiralerspong, M.W. Bojanowski, M. Pandolfo (1999). Knock-out of the CyaY gene in Escherichia coli does not affect cellular iron content to sensitivity of oxidants. FEBS lett. 456: 13-16

Uchida, T., N. Kobayashi, S. Muneta, and K. Ishimori. (2017). The Iron Chaperone Protein CyaY from Vibrio cholerae Is a Heme-Binding Protein. Biochemistry 56: 2425-2434.


TC#NameOrganismal TypeExample

Frataxin (Fxn; FrdA) of 210 aas. Defective in the inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism (Chiang et al. 2016).


Frataxin of Homo sapiens (Q16595)


Frataxin homologue, Yfh1, of 174 aas.  Promotes the biosynthesis of heme as well as the assembly and repair of iron-sulfur clusters by delivering Fe2+ to proteins involved in these pathways. It also plays a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe2+ to Fe3+. It can store large amounts of the metal in the form of a ferrihydrite mineral by oligomerization and may be involved in the regulation of the mitochondrial electron transport chain (Karlberg et al. 2006).

Yfh1 of Saccharomyces cerevisiae (Baker's yeast)


TC#NameOrganismal TypeExample

The CyaY protein of 106 aas is an iron transport protein for iron-sulfur (Fe-S) cluster biosynthetic systems (Uchida et al. 2017). It also transports iron to ferrochelatase that catalyzes insertion of Fe2+ into protoporphyrin IX. Uchida et al. 2017 found that CyaY has the ability to bind heme as well as iron.


CyaY of E. coli (P27838)