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Structure and mechanism of a primate ferroportin

By Zhenning Ren, Shuai Gao, Jiemin Shen, Lie Wang, Zhichun Xu, Ye Yu, Preetham Bachina, Hanzhi Zhang, Arthur Laganowsky, Nieng Yan, Ming Zhou, Yaping Pan

Posted 05 Mar 2020
bioRxiv DOI: 10.1101/2020.03.04.975748

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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