title: Understanding the binding properties of an unusual metal-binding protein--a study of bacterial frataxin.
abstract: Deficiency of the small mitochondrial protein frataxin causes Friedreich's ataxia, a severe neurodegenerative pathology. Frataxin, which has been highly conserved throughout evolution, is thought to be involved in, among other processes, Fe-S cluster formation. Independent evidence shows that it binds iron directly, although with very distinct features and low affinity. Here, we have carried out an extensive study of the binding properties of CyaY, the bacterial ortholog of frataxin, to different divalent and trivalent cations, using NMR and X-ray crystallography. We demonstrate that the protein has low cation specificity and contains multiple binding sites able to chelate divalent and trivalent metals with low affinity. Binding does not involve cavities or pockets, but exposed glutamates and aspartates, which are residues that are unusual for iron chelation when not assisted by histidines and/or cysteines. We have related how such an ability to bind cations on a relatively large area through an electrostatic mechanism could be a valuable asset for protein function.
authors.affiliation: National Institute for Medical Research, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastore
authors.forename: Marisa
authors.initials: M
authors.lastname: Franzese
authors.forename: Filomena
authors.initials: F
authors.lastname: Sica
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Temussi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005682:Gadolinium / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D028581:Lanthanoid Series Elements / Q000737:chemistry / Q000378:metabolism; D008187:Lutetium / Q000737:chemistry / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D000096923:Frataxin
chemical_list: D001426:Bacterial Proteins; D003035:Cobalt; D005682:Gadolinium; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D028581:Lanthanoid Series Elements; D008187:Lutetium; D008274:Magnesium; D008670:Metals; D015032:Zinc; D000096923:Frataxin