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.
Highlights
Ferroportin is an iron exporter essential for releasing cellular iron into circulation
More than 60 mutations in Fpn are associated with ferroportin diseases in human[5,6], indicating an important physiological role of Fpn in iron homeostasis
We expressed and purified Fpns from human and from Philippine tarsier (Tarcius syrichta or Carlito syrichta; TsFpn), which is 92% identical and 98% similar to human Fpn, and we demonstrated that Fpn is an electroneutral H+/Fe2+ antiporter
Summary
Ferroportin is an iron exporter essential for releasing cellular iron into circulation. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. 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. Structures of a bacterial homolog of Fpn (Bdellovibrio bacteriovorous; BbFpn) in both the inward- and outward-facing conformations were reported recently[21,22], which significantly enhances our understanding of Fpn. given the modest sequence identity (~20%) and similarity (49%) between BbFpn and human Fpn, structures of mammalian Fpn are required to address questions on interactions with hepcidin and binding and transport of metal ions. We determined structures of TsFpn in the presence of Co2+ or hepcidin, and the structures define two metal ion binding sites as well as the hepcidin binding pocket
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