title: Molecular details of the yeast frataxin-Isu1 interaction during mitochondrial Fe-S cluster assembly.
abstract: Frataxin, a conserved nuclear-encoded mitochondrial protein, plays a direct role in iron-sulfur cluster biosynthesis within the ISC assembly pathway. Humans with frataxin deficiency have Friedreich's ataxia, a neurodegenerative disorder characterized by mitochondrial iron overload and disruption in Fe-S cluster synthesis. Biochemical and genetic studies have shown frataxin interacts with the iron-sulfur cluster assembly scaffold protein (in yeast, there are two, Isu1 and Isu2), indicating frataxin plays a direct role in cluster assembly, possibly by serving as an iron chaperone in the assembly pathway. Here we provide molecular details of how yeast frataxin (Yfh1) interacts with Isu1 as a structural module to improve our understanding of the multiprotein complex assembly that completes Fe-S cluster assembly; this complex also includes the cysteine desulfurase (Nfs1 in yeast) and the accessory protein (Isd11), together in the mitochondria. Thermodynamic binding parameters for protein partner and iron binding were measured for the yeast orthologs using isothermal titration calorimetry. Nuclear magnetic resonance spectroscopy was used to provide the molecular details to understand how Yfh1 interacts with Isu1. X-ray absorption studies were used to electronically and structurally characterize how iron is transferred to Isu1 and then incorporated into an Fe-S cluster. These results were combined with previously published data to generate a structural model for how the Fe-S cluster protein assembly complex can come together to accomplish Fe-S cluster assembly.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Cook
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Kondapalli
authors.forename: Swati
authors.initials: S
authors.lastname: Rawat
authors.forename: William C
authors.initials: WC
authors.lastname: Childs
authors.forename: Yogapriya
authors.initials: Y
authors.lastname: Murugesan
authors.forename: Andrew
authors.initials: A
authors.lastname: Dancis
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Stemmler
mesh_terms: D002151:Calorimetry; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D056928:X-Ray Absorption Spectroscopy; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C121520:ISU1 protein, S cerevisiae
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