Mechanism of Ca²⁺ transport by ferroportin

Ferroportin (Fpn) is a transporter that releases Fe²⁺ from cells and is important for iron homeostasis in circulation. Export of Fe²⁺ by Fpn is coupled to import of H⁺ to maintain charge balance. Although Ca²⁺ was shown to modulate Fe²⁺ transport in Fpn, transport of Ca²⁺ by Fpn has not been demonstrated. Here we show that human Fpn (HsFpn) mediates Ca²⁺ transport, and that the Ca²⁺ transport does not rely on the transport of other ions. 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 inhibited in the presence of Fe²⁺ but not vice versa. Function of Fpn as a Ca²⁺ uniporter in the absence of Fe²⁺ provides a molecular basis for regulations of iron homeostasis by Ca²⁺.