Structure of human ferroportin reveals molecular basis of iron homeostasis

The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin negatively regulates iron absorption and iron recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias. The molecular basis of ferroportin-mediated iron transport and regulation by hepcidin remain incompletely understood. Here, we combine cryo-electron microscopy, molecular dynamics simulations, and biochemical experiments to decipher molecular details of iron recognition and hepcidin binding to ferroportin. Iron binds to a conserved cavity in the C-domain of ferroportin, in a site unique within the broader major facilitator superfamily of transporters. We further show that hepcidin binding to ferroportin is allosterically coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. Hepcidin binds to the outward open conformation of ferroportin in a region adjacent to the iron-binding site in the C-domain. These results suggest a new model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.