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

• Published in: Nature communications Vol. 9; no. 1; pp. 3075 - 10
• Main Authors: Deshpande, Chandrika N., Ruwe, T. Alex, Shawki, Ali, Xin, Vicky, Vieth, Kyle R., Valore, Erika V., Qiao, Bo, Ganz, Tomas, Nemeth, Elizabeta, Mackenzie, Bryan, Jormakka, Mika
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/321/1154; 631/45/535/1266; 631/57/2283; 64/114; 82/80; 82/83; Animals; Binding Sites; Blood plasma; Calcium; Calcium (blood); Calcium (extracellular); Calcium - chemistry; Calcium homeostasis; Calcium ions; Cation Transport Proteins - chemistry; Chelating Agents - chemistry; Crystal structure; Crystallography, X-Ray; Efflux; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Iron; Iron - chemistry; Medicine; Metabolism; Metals - chemistry; multidisciplinary; Mutagenesis; Oocytes - metabolism; Physiology; Placenta; Protein Conformation; Science; Science (multidisciplinary); Substrates; Transport; Xenopus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05446-4

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 Ca 2+ is required for human Fpn transport activity. Whereas iron efflux is stimulated by extracellular Ca 2+ in the physiological range, Ca 2+ is not transported. We determine the crystal structure of a Ca 2+ -bound BbFpn, a prokaryotic orthologue, and find that Ca 2+ 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. Ferroportin (Fpn) is essential for mammalian iron homeostasis as it exports iron from cells into blood circulation, but the molecular mechanisms of Fpn-mediated iron transport remain obscure. Here the authors use biophysical approaches to reveal that Ca 2+ is a required cofactor for Fpn transport activity.