Calcium is an essential cofactor for metal efflux by the ferroportin transporter family

Chandrika N. Deshpande, T. Alex Ruwe, Ali Shawki, Vicky Xin, Kyle R. Vieth, Erika V. Valore, Bo Qiao, Tomas Ganz, Elizabeta Nemeth, Bryan Mackenzie () and Mika Jormakka ()
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Chandrika N. Deshpande: Centenary Institute, Sydney Medical School, University of Sydney
T. Alex Ruwe: University of Cincinnati College of Medicine
Ali Shawki: University of Cincinnati College of Medicine
Vicky Xin: Centenary Institute, Sydney Medical School, University of Sydney
Kyle R. Vieth: University of Cincinnati College of Medicine
Erika V. Valore: David Geffen School of Medicine at University of California
Bo Qiao: David Geffen School of Medicine at University of California
Tomas Ganz: David Geffen School of Medicine at University of California
Elizabeta Nemeth: David Geffen School of Medicine at University of California
Bryan Mackenzie: University of Cincinnati College of Medicine
Mika Jormakka: Centenary Institute, Sydney Medical School, University of Sydney

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Ferroportin (Fpn)—the only known cellular iron exporter—transports dietary and recycled iron into the blood plasma, and transfers iron across the placenta. Despite its central role in iron metabolism, our molecular understanding of Fpn-mediated iron efflux remains incomplete. Here, we report that Ca2+ is required for human Fpn transport activity. Whereas iron efflux is stimulated by extracellular Ca2+ in the physiological range, Ca2+ is not transported. We determine the crystal structure of a Ca2+-bound BbFpn, a prokaryotic orthologue, and find that Ca2+ is a cofactor that facilitates a conformational change critical to the transport cycle. We also identify a substrate pocket accommodating a divalent transition metal complexed with a chelator. These findings support a model of iron export by Fpn and suggest a link between plasma calcium and iron homeostasis.

Date: 2018
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DOI: 10.1038/s41467-018-05446-4

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