Mechanism of Ca ²⁺ transport by ferroportin

Ferroportin (Fpn) is a transporter that releases Fe ²⁺ from cells and is important for iron homeostasis in circulation. Export of Fe ²⁺ by Fpn is coupled to import of H ⁺ to maintain charge balance. Although Ca ²⁺ was shown to modulate Fe ²⁺ transport in Fpn, transport of Ca ²⁺ by Fpn has not been demonstrated. Here we show that human Fpn (HsFpn) mediates Ca ²⁺ transport, and that the Ca ²⁺ transport does not rely on the transport of other ions. We determine the structure of Ca ²⁺ -bound HsFpn and identify a single Ca ²⁺ binding site distinct from the Fe ²⁺ binding sites. Further studies validate the Ca ²⁺ binding site and show that Ca ²⁺ transport is inhibited in the presence of Fe ²⁺ but not vice versa . Function of Fpn as a Ca ²⁺ uniporter in the absence of Fe ²⁺ provides a molecular basis for regulations of iron homeostasis by Ca ²⁺ .