Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Calcium is a required cofactor for metal efflux by the ferroportin transporter family (#163)

Chandrika N Deshpande 1 , T. Alex Ruwe 2 , Ali Shawki 2 , Vicky Xin 3 , Kyle R Vieth 2 , Erika V Valore 4 , Bo Qiao 4 , Tomas Ganz 4 , Elizabeta Nemeth 4 , Bryan Mackenzie 2 , Mika Jormakka 3
  1. Drug Discovery Initiative, Sydney Analytical, Core Research Facilities, The University of Sydney, Sydney, NSW, Australia
  2. Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
  3. Structural Biology Program, Centenary Institute, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
  4. Department of Medicine, David Geffen School of Medicine, , University of California, Los Angeles, CA, USA

Iron is vital to the survival of almost all living organisms given it is an essential component in multitude of proteins with diverse biological functions. In mammalian system,  iron homeostasis is critical, 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 exporter of cellular iron and is responsible for its entry from intracellular storage into plasma for circulation.                                                                                                                                                                                                                                                                                                                                                                                                 

 Despite its central role in iron metabolism, our molecular understanding of FPN-mediated iron transport remains incomplete. In our recently published work1, we have shown by combining transport and biophysical studies, that FPN is a Ca2+ dependent iron transporter. 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. We have identified a substrate pocket in BbFPN accommodating a Ni-EDTA complex, thus proposing a more complex transport model for the Fpn proteins in which they bind and transport metal in complex with an anion or a poly-carboxylate metabolite. These findings advance our current understanding of FPN-mediated iron efflux and have fundamental implications for developing targeted strategies to manipulate FPN therapeutically.

  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. Nature Communications, August 2018.