The hepcidin-binding site on ferroportin is evolutionarily conserved.
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 degrees 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.
De Domenico
Ivana
I
Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Nemeth
Elizabeta
E
Nelson
Jenifer M
JM
Phillips
John D
JD
Ajioka
Richard S
RS
Kay
Michael S
MS
Kushner
James P
JP
Ganz
Tomas
T
Ward
Diane M
DM
Kaplan
Jerry
J
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism*; D001001:Anura / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence / Q000502:physiology; D019143:Evolution, Molecular; D005399:Fishes / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D013045:Species Specificity; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D010455:Peptides; D000098742:Ferroportin; D007501:Iron