title: Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin.
abstract: In vertebrates, the iron exporter ferroportin releases Fe(2+) from cells into plasma, thereby maintaining iron homeostasis. The transport activity of ferroportin is suppressed by the peptide hormone hepcidin, which exhibits upregulated expression in chronic inflammation, causing iron-restrictive anaemia. However, due to the lack of structural information about ferroportin, the mechanisms of its iron transport and hepcidin-mediated regulation remain largely elusive. Here we report the crystal structures of a putative bacterial homologue of ferroportin, BbFPN, in both the outward- and inward-facing states. Despite undetectable sequence similarity, BbFPN adopts the major facilitator superfamily fold. A comparison of the two structures reveals that BbFPN undergoes an intra-domain conformational rearrangement during the transport cycle. We identify a substrate metal-binding site, based on structural and mutational analyses. Furthermore, the BbFPN structures suggest that a predicted hepcidin-binding site of ferroportin is located within its central cavity. Thus, BbFPN may be a valuable structural model for iron homeostasis regulation by ferroportin.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.|Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Reiya
authors.initials: R
authors.lastname: Taniguchi
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.|Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Hideaki E
authors.initials: HE
authors.lastname: Kato
authors.affiliation: Structural Biology Program, Centenary Institute, Locked Bag 6, Sydney, New South Wales 2042, Australia.|Faculty of Medicine, Central Clinical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Josep
authors.initials: J
authors.lastname: Font
authors.affiliation: Structural Biology Program, Centenary Institute, Locked Bag 6, Sydney, New South Wales 2042, Australia.|Faculty of Medicine, Central Clinical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Chandrika N
authors.initials: CN
authors.lastname: Deshpande
authors.affiliation: Technical office, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Wada
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba 277-8562, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.|Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Structural Biology Program, Centenary Institute, Locked Bag 6, Sydney, New South Wales 2042, Australia.|Faculty of Medicine, Central Clinical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Mika
authors.initials: M
authors.lastname: Jormakka
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.|Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
mesh_terms: D001501:Bdellovibrio / Q000378:metabolism*; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D011487:Protein Conformation; D040681:Structural Homology, Protein; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron