Mechanism of Ca2+ transport by ferroportin

Abstract

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+.