Mechanism of Ca²⁺ transport by ferroportin

Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe²⁺) from cells and is important for homeostasis of iron in circulation. Export of one Fe²⁺ by Fpn is coupled to import of two H⁺ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca²⁺ transport. We determine the structure of Ca²⁺-bound HsFpn and identify a single Ca²⁺ binding site distinct from the Fe²⁺ binding sites. Further studies validate the Ca²⁺ binding site and show that Ca²⁺ transport is not coupled to transport of another ion. In addition, Ca²⁺ transport is significantly inhibited in the presence of Fe²⁺ but not vice versa. Function of Fpn as a Ca²⁺ uniporter may allow regulation of iron homeostasis by Ca²⁺.