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).