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Structural basis of ion transport and inhibition in ferroportin.

<div class='caption-title'>Function of purified TsFpn.</div>
<div class='caption-title'>Structure of TsFpn.</div>
<div class='caption-title'>Two ion binding sites in TsFpn.</div>
Pan Y, Ren Z, Gao S, Shen J, Wang L, Xu Z, Yu Y, Bachina P, Zhang H, Fan X, Laganowsky A, Yan N, Zhou M
OpenAccess logo Nat Commun 11 5686 (2020)
Cited: 25 times
EuropePMC logo PMID: 33173040

Abstract

Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H+/Fe2+ antiporter so that transport of each Fe2+ is coupled to transport of two H+ in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H+ and Fe2+. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases.

Articles - 6vyh mentioned but not cited (6)

  1. Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS). Drew D, North RA, Nagarathinam K, Tanabe M. Chem Rev 121 5289-5335 (2021)
  2. Mechanism of Ca2+ transport by ferroportin. Shen J, Wilbon AS, Zhou M, Pan Y. Elife 12 e82947 (2023)
  3. Insights into the Role of the Discontinuous TM7 Helix of Human Ferroportin through the Prism of the Asp325 Residue. Le Tertre M, Elbahnsi A, Ka C, Callebaut I, Le Gac G. Int J Mol Sci 22 6412 (2021)
  4. Structural basis of ferroportin inhibition by minihepcidin PR73. Wilbon AS, Shen J, Ruchala P, Zhou M, Pan Y. PLoS Biol 21 e3001936 (2023)
  5. Structures of ferroportin in complex with its specific inhibitor vamifeport. Lehmann EF, Liziczai M, Drożdżyk K, Altermatt P, Langini C, Manolova V, Sundstrom H, Dürrenberger F, Dutzler R, Manatschal C. Elife 12 e83053 (2023)
  6. Using deep-learning predictions of inter-residue distances for model validation. Sánchez Rodríguez F, Chojnowski G, Keegan RM, Rigden DJ. Acta Crystallogr D Struct Biol 78 1412-1427 (2022)


Reviews citing this publication (9)

  1. Iron metabolism in infections: Focus on COVID-19. Girelli D, Marchi G, Busti F, Vianello A. Semin Hematol 58 182-187 (2021)
  2. Molecular Mechanisms of Iron and Heme Metabolism. Dutt S, Hamza I, Bartnikas TB. Annu Rev Nutr 42 311-335 (2022)
  3. Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin. Gammella E, Correnti M, Cairo G, Recalcati S. Int J Mol Sci 22 2986 (2021)
  4. Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects. Pasquadibisceglie A, Bonaccorsi di Patti MC, Musci G, Polticelli F. Biomolecules 13 1172 (2023)
  5. Novel monodisperse FePt nanocomposites for T2-weighted magnetic resonance imaging: biomedical theranostics applications. Chang ZX, Li CH, Chang YC, Huang CF, Chan MH, Hsiao M. Nanoscale Adv 4 377-386 (2022)
  6. Cryo-EM as a powerful tool for drug discovery: recent structural based studies of SARS-CoV-2. Kim HU, Jung HS. Appl Microsc 51 13 (2021)
  7. Iron-Induced Oxidative Stress in Human Diseases. Kawabata T. Cells 11 2152 (2022)
  8. Mechanisms controlling cellular and systemic iron homeostasis. Galy B, Conrad M, Muckenthaler M. Nat Rev Mol Cell Biol (2023)
  9. Structures and coordination chemistry of transporters involved in manganese and iron homeostasis. Ray S, Gaudet R. Biochem Soc Trans 51 897-923 (2023)

Articles citing this publication (10)

  1. RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation. Jiang L, Wang J, Wang K, Wang H, Wu Q, Yang C, Yu Y, Ni P, Zhong Y, Song Z, Xie E, Hu R, Min J, Wang F. Blood 138 689-705 (2021)
  2. Cryo-EM structure of human glucose transporter GLUT4. Yuan Y, Kong F, Xu H, Zhu A, Yan N, Yan C. Nat Commun 13 2671 (2022)
  3. Extracellular domain of PepT1 interacts with TM1 to facilitate substrate transport. Shen J, Hu M, Fan X, Ren Z, Portioli C, Yan X, Rong M, Zhou M. Structure 30 1035-1041.e3 (2022)
  4. Footprinting Mass Spectrometry of Membrane Proteins: Ferroportin Reconstituted in Saposin A Picodiscs. Zhou F, Yang Y, Chemuru S, Cui W, Liu S, Gross M, Li W. Anal Chem 93 11370-11378 (2021)
  5. Comparative analysis of the functional properties of human and mouse ferroportin. Azucenas CR, Ruwe TA, Bonamer JP, Qiao B, Ganz T, Jormakka M, Nemeth E, Mackenzie B. Am J Physiol Cell Physiol (2023)
  6. Elevated SLC40A1 impairs cardiac function and exacerbates mitochondrial dysfunction, oxidative stress, and apoptosis in ischemic myocardia. Feng R, Wang D, Li T, Liu X, Peng T, Liu M, Ren G, Xu H, Luo H, Lu D, Qi B, Zhang M, Li Y. Int J Biol Sci 20 414-432 (2024)
  7. Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter. Lambert E, Mehdipour AR, Schmidt A, Hummer G, Perez C. Nat Commun 13 1022 (2022)
  8. Genetic Incorporation of Dansylalanine in Human Ferroportin to Probe the Alternating Access Mechanism of Iron Transport. Amadei M, Niro A, Fullone MR, Miele R, Polticelli F, Musci G, Bonaccorsi di Patti MC. Int J Mol Sci 24 11919 (2023)
  9. Hyperferritinemia Is a Predictor of Onset of Diabetes in Japanese Males Independently of Decreased Renal Function and Fatty Liver: A Fifteen-Year Follow-Up Study. Sakuma Y, Ogino J, Iwai R, Inoue T, Takahashi H, Suzuki Y, Kinoshita D, Takemura K, Takahashi H, Shimura H, Sato Y, Yoshida S, Hashimoto N. J Clin Med Res 13 541-548 (2021)
  10. Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation. Dufrusine B, Valentinuzzi S, Bibbò S, Damiani V, Lanuti P, Pieragostino D, Del Boccio P, D'Alessandro E, Rabottini A, Berghella A, Allocati N, Falasca K, Ucciferri C, Mucedola F, Di Perna M, Martino L, Vecchiet J, De Laurenzi V, Dainese E. Int J Mol Sci 24 15 (2022)


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