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

Deshpande C1,2, Ruwe T3,4, Shawki A3,4, Xin V2, Vieth K3, Valore E5, Ganz T5, Nemeth E5, Mackenzie B3,4 and Jormakka M2,6

  1. Protein Production, Drug Discovery, Sydney Analytical, Core Research Facilities, The University of Sydney.
  2. Structural Biology Program, Centenary Institute, Sydney.
  3. Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  4. Systems Biology & Physiology Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  5. Department of Medicine and 6Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
  6. Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.

Iron is essential for almost all living organisms owing to its involvement in a number of metabolic and catalytic processes. Iron metabolism is critical in mammalian system and both iron deficiency and overload can account for some of the most common human diseases, such as iron-restricted anemia and hemochromatoses. To date, Ferroportin (FPN) is the only known mammalian iron exporter and is responsible for the entry of iron from intracellular storage into plasma for circulation. Despite its central role in iron metabolism, our molecular understanding of FPN-mediated iron efflux remains incomplete. We have shown by combining transport and biophysical studies, that FPN is a Ca2+ dependent iron transporter (1). In addition, we have determined the crystal structure of a Ca2+-bound BbFPN protein (a prokaryotic homolog of FPN), revealing a marked Ca2+-induced conformational change. Our results have demonstrated that Ca2+ is a required cofactor in FPN-mediated metal efflux. We also provide novel insights into the substrate binding pocket of FPN. Our findings provide important conceptual advancements in the understanding of FPN-mediated iron efflux and have fundamental implications for developing strategies to manipulate FPN therapeutically. {Reference 1) 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, Mika Jormakka (Accepted in principle with final editorial revisions, Nature Communications. 2018)}.