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bioRxiv · 10.1101/2020.03.04.975748

Structure and mechanism of a primate ferroportin

Ren, Z.·Gao, S.·Shen, J.·Wang, L.·Xu, Z.·Yu, Y.·Bachina, P.·Zhang, H.·Laganowsky, A.·Yan, N.·Zhou, M.·Pan, Y.
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Abstract

Ferroportin is the only cellular iron exporter in human and essential for iron homoeostasis. Mutations in ferroportin are associated with hemochromatosis or 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 by ferroportin and its regulation by hepcidin remains unclear. Here we present the structure of a ferroportin from the primate Philippine tarsier (TsFpn) at 3.0 [A] resolution determined 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 with each site 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 such that the transport cycle is electroneutral. Further studies show that the two ion binding sites affect transport of H+ and Fe2+ differently. The structure also provides mechanistic interpretation for mutations that cause ferroportin diseases.

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Ren, Z., Gao, S., Shen, J., Wang, L., Xu, Z., Yu, Y., Bachina, P., Zhang, H., Laganowsky, A., Yan, N., Zhou, M., Pan, Y.. 2020-03-05. Structure and mechanism of a primate ferroportin. https://doi.org/10.1101/2020.03.04.975748

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