title: Effector role reversal during evolution: the case of frataxin in Fe-S cluster biosynthesis.
abstract: Human frataxin (FXN) has been intensively studied since the discovery that the FXN gene is associated with the neurodegenerative disease Friedreich's ataxia. Human FXN is a component of the NFS1-ISD11-ISCU2-FXN (SDUF) core Fe-S assembly complex and activates the cysteine desulfurase and Fe-S cluster biosynthesis reactions. In contrast, the Escherichia coli FXN homologue CyaY inhibits Fe-S cluster biosynthesis. To resolve this discrepancy, enzyme kinetic experiments were performed for the human and E. coli systems in which analogous cysteine desulfurase, Fe-S assembly scaffold, and frataxin components were interchanged. Surprisingly, our results reveal that activation or inhibition by the frataxin homologue is determined by which cysteine desulfurase is present and not by the identity of the frataxin homologue. These data are consistent with a model in which the frataxin-less Fe-S assembly complex exists as a mixture of functional and nonfunctional states, which are stabilized by binding of frataxin homologues. Intriguingly, this appears to be an unusual example in which modifications to an enzyme during evolution inverts or reverses the mode of control imparted by a regulatory molecule.
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, Texas, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bridwell-Rabb
authors.forename: Clara
authors.initials: C
authors.lastname: Iannuzzi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: David P
authors.initials: DP
authors.lastname: Barondeau
mesh_terms: D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013455:Sulfur / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D013437:Carbon-Sulfur Lyases; D029968:Escherichia coli Proteins; D007501:Iron; D033862:Iron-Binding Proteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D013455:Sulfur; D000096923:Frataxin; C120906:CyaY protein, E coli; C411665:IscU protein, E coli; C544445:LYRM4 protein, human; C513492:NFS1 protein, human; C080546:cysteine desulfurase