Structural basis of ion transport and inhibition in ferroportin
Autor: | Ming Zhou, Nieng Yan, Xiao Fan, Zhenning Ren, Hanzhi Zhang, Jiemin Shen, Ye Yu, Shuai Gao, Arthur Laganowsky, Preetham Bachina, Zhichun Xu, Lie Wang, Yaping Pan |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
inorganic chemicals congenital hereditary and neonatal diseases and abnormalities Iron Antiporter Science Ferroportin General Physics and Astronomy Plasma protein binding Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Ion binding Hepcidins Cryoelectron microscopy Hepcidin hemic and lymphatic diseases medicine Animals Humans Binding site lcsh:Science Cation Transport Proteins Ion transporter Binding Sites Ion Transport Multidisciplinary Anemia Iron-Deficiency biology Chemistry Proteins nutritional and metabolic diseases General Chemistry Iron deficiency medicine.disease Cell biology 030104 developmental biology biology.protein lcsh:Q 030217 neurology & neurosurgery Protein Binding |
Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-11 (2020) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. Ferroportin is an iron exporter essential for releasing cellular iron into circulation and is inhibited by a peptide hormone, hepcidin. Here authors present cryo-EM structures of the ferroportin from the primate Philippine tarsier (TsFpn) with and without hepcidin and show that TsFpn is an electroneutral H+ /Fe2+ antiporter. |
Databáze: | OpenAIRE |
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