The hepcidin-binding site on ferroportin is evolutionarily conserved |
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Authors: | De Domenico Ivana Nemeth Elizabeta Nelson Jenifer M Phillips John D Ajioka Richard S Kay Michael S Kushner James P Ganz Tomas Ward Diane M Kaplan Jerry |
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Affiliation: | 1Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA;2Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;3Division of Hematology and Bone Marrow Transplantation, University of Utah, Salt Lake City, UT 84132, USA;4Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA |
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Abstract: | Mammalian iron homeostasis is regulated by the interaction of the liver-produced peptide hepcidin and its receptor, the iron transporter ferroportin. Hepcidin binds to ferroportin resulting in degradation of ferroportin and decreased cellular iron export. We identify the hepcidin-binding domain (HBD) on ferroportin and show that a synthetic 19 amino acid peptide corresponding to the HBD recapitulates the characteristics and specificity of hepcidin binding to cell-surface ferroportin. The binding of mammalian hepcidin to ferroportin or the HBD shows an unusual temperature dependency with an increased rate of dissociation at temperatures below 15°C. The increased rate of dissociation is due to temperature- dependent changes in hepcidin structure. In contrast, hepcidin from poikilothermic vertebrates, such as fish or frogs, binds the HBD in a temperature-independent fashion. The affinity of hepcidin for the HBD permits a rapid, sensitive assay of hepcidin from all species and yields insights into the evolution of hepcidin. |
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Keywords: | HUMDISEASE EVO_ECOL |
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