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Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis

By Christian B. Billesbølle, Caleigh M Azumaya, Rachael C. Kretsch, Alexander S Powers, Shane Gonen, Simon Schneider, Tara Arvedson, Ron O. Dror, Yifan Cheng, Aashish Manglik

Posted 18 Mar 2020
bioRxiv DOI: 10.1101/2020.03.16.993006

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 recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias. Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two divalent metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway. The carboxy-terminus of hepcidin directly contacts the divalent metal in the FPN C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. 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. ### Competing Interest Statement Tara Arvedson is employed by Amgen and reports Amgen stock. None of the other authors report conflicts of interest.

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