Ferroportin is the only cellular iron exporter in human and essential for iron homoeostasis. Mutations in ferroportin cause ferroportin diseases characterized by a paradoxical combination of anemia and abnormal accumulation of iron in cells. Ferroportin is also the target of hepcidin, which is a hormone that downregulates ferroportin activity. However, due to a lack of three-dimensional structures, the mechanism of iron transport in ferroportin and its regulation by hepcidin remains unclear. Here we present the structure of a ferroportin from the primate Tarsius syrichta (TsFpn) at 3.0 angstrom resolution solved by cryo-electron microscopy. TsFpn has a structural fold common to major facilitator superfamily of transporters and the current structure is in an outward-open conformation. The structure identifies two potential ion binding sites and each site is coordinated by two residues. Functional studies demonstrate that TsFpn is a H+/Fe2+ antiporter and that transport of one Fe2+ is coupled to the transport of two H+ in the opposite direction so that the transport cycle is electroneutral. Mutation to one of the sites mainly affect H+ transport while mutation to the other site affects both Fe2+ and H+ transport. The structure also provides mechanistic interpretation for mutations that cause ferroportin diseases.
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