Structure, function and assembly of frataxin oligomers

Iron is an essential part of prosthetic groups such as heme and iron-sulphur clusters, which are involved in various redox reactions of central importance for life. Iron is not easily available to organisms, mainly due to the extremely low solubility (around 10^-18 M) of its most common form, Fe³⁺. The Fe²⁺ variant has a much higher solubility (approximately 10^-10 M); however, it is easily oxidized by atmospheric oxygen to Fe³⁺. Fe²⁺ may also be toxic to organisms, since it can promote the generation of highly reactive oxygen species that are capable of causing severe damage to proteins and nucleic acids. Thus, to maintain an adequate supply of iron, cells require molecular mechanisms to overcome both the limited bioavailability and the potential toxicity of this metal.

Two tightly regulated biochemical processes, metallation of porphyrin at the last stage of heme biosynthesis and the generation of iron-sulphur clusters (ISC), take place inside the mitochondrial matrix and utilise around 80% of the iron acquired by organisms. The proteins, frataxin, ferrochelatase and IscU, are central for these processes. Frataxin may either make iron available to ferrochelatase and IscU, thereby acting as an iron chaperone, or convert surplus iron in the mitochondrion to a mineral, providing a mechanism for iron storage and detoxification, similar to the mechanism of ferritin. Ferrochelatase catalyses iron insertion into protoporphyrin IX at the terminal step of heme biosynthesis, while IscU assists in the formation of iron-sulphur clusters.

We have determined the crystal structure of yeast frataxin trimer (Karlberg et al., 2006) as well as the structure of the iron-loaded 24-subunit particle using electron microscopy and single particle reconstruction (Schagerlöf et al., 2008). Currently we focus on the study of the process of assembly of frataxin oligomers using methods like small-angle X-ray scattering, analytical ultracentrifugation and gel filtration.