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Structural and functional characterization of a frataxin from a thermophilic organism

DOI: 10.1111/febs.14750 DOI Help

Authors: Masooma Rasheed (King's College London) , Mostafa Jamshidiha (Imperial College London) , Rita Puglisi (King's College London) , Robert Yan (King's College London) , Ernesto Cota (Imperial College London) , Annalisa Pastore (King's College London; University of Pavia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Febs Journal

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 17221

Abstract: Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron‐sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation of the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable amongst the frataxin orthologues. We also characterized the iron‐binding mode of C. thermophilum frataxin and demonstrated that it binds it through a semi‐conserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron‐sulfur cluster synthesis, and act as its inhibitor.

Journal Keywords: Friedreich's ataxia; iron‐sulfur clusters; structural biology

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography