The Hepcidin-binding Site on Ferroportin is Evolutionarily Conserved

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2008 Aug 6

PMID 18680715

Citations 56

Authors

Ivana De Domenico

Elizabeta Nemeth

Jenifer M Nelson

John D Phillips

Richard S Ajioka

Michael S Kay

James P Kushner

Tomas Ganz

Diane M Ward

Jerry Kaplan

Affiliations

Soon will be listed here.

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 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.

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References

De Domenico I, Ward D, Nemeth E, Vaughn M, Musci G, Ganz T . The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A. 2005; 102(25):8955-60. PMC: 1157058. DOI: 10.1073/pnas.0503804102. View

Liu X, Yang F, Haile D . Functional consequences of ferroportin 1 mutations. Blood Cells Mol Dis. 2005; 35(1):33-46. DOI: 10.1016/j.bcmd.2005.04.005. View

De Domenico I, Ward D, Musci G, Kaplan J . Iron overload due to mutations in ferroportin. Haematologica. 2006; 91(1):92-5. PMC: 3718253. View

Park C, Valore E, Waring A, Ganz T . Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2000; 276(11):7806-10. DOI: 10.1074/jbc.M008922200. View

Murphy A, Witcher D, Luan P, Wroblewski V . Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry. Blood. 2007; 110(3):1048-54. DOI: 10.1182/blood-2006-11-057471. View

De Domenico I, Ward D, Langelier C, Vaughn M, Nemeth E, Sundquist W . The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007; 18(7):2569-78. PMC: 1924807. DOI: 10.1091/mbc.e07-01-0060. View

Nicolas G, Chauvet C, Viatte L, Danan J, Bigard X, Devaux I . The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002; 110(7):1037-44. PMC: 151151. DOI: 10.1172/JCI15686. View

Lou D, Nicolas G, Lesbordes J, Viatte L, Grimber G, Szajnert M . Functional differences between hepcidin 1 and 2 in transgenic mice. Blood. 2003; 103(7):2816-21. DOI: 10.1182/blood-2003-07-2524. View

Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya H, Umehara H . Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood. 2006; 108(4):1381-7. DOI: 10.1182/blood-2005-10-4043. View

10.

Huang P, Chen J, Kuo C . Three different hepcidins from tilapia, Oreochromis mossambicus: analysis of their expressions and biological functions. Mol Immunol. 2006; 44(8):1922-34. DOI: 10.1016/j.molimm.2006.09.031. View

11.

Donovan A, Lima C, Pinkus J, Pinkus G, Zon L, Robine S . The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005; 1(3):191-200. DOI: 10.1016/j.cmet.2005.01.003. View

12.

Sham R, Phatak P, West C, Lee P, Andrews C, Beutler E . Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol Dis. 2005; 34(2):157-61. DOI: 10.1016/j.bcmd.2004.12.002. View

13.

Shi J, Camus A . Hepcidins in amphibians and fishes: Antimicrobial peptides or iron-regulatory hormones?. Dev Comp Immunol. 2005; 30(9):746-55. DOI: 10.1016/j.dci.2005.10.009. View

14.

Ilyin G, Courselaud B, Troadec M, Pigeon C, Alizadeh M, Leroyer P . Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and co-inducibility during iron overload. FEBS Lett. 2003; 542(1-3):22-6. DOI: 10.1016/s0014-5793(03)00329-6. View

15.

Ganz T, Nemeth E . Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta. 2006; 1763(7):690-9. DOI: 10.1016/j.bbamcr.2006.03.014. View

16.

Kemna E, Tjalsma H, Podust V, Swinkels D . Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007; 53(4):620-8. DOI: 10.1373/clinchem.2006.079186. View

17.

Padhi A, Verghese B . Evidence for positive Darwinian selection on the hepcidin gene of Perciform and Pleuronectiform fishes. Mol Divers. 2007; 11(3-4):119-30. DOI: 10.1007/s11030-007-9066-4. View

18.

Kemna E, Tjalsma H, Laarakkers C, Nemeth E, Willems H, Swinkels D . Novel urine hepcidin assay by mass spectrometry. Blood. 2005; 106(9):3268-70. DOI: 10.1182/blood-2005-05-1873. View

19.

Lauth X, Babon J, Stannard J, Singh S, Nizet V, Carlberg J . Bass hepcidin synthesis, solution structure, antimicrobial activities and synergism, and in vivo hepatic response to bacterial infections. J Biol Chem. 2004; 280(10):9272-82. DOI: 10.1074/jbc.M411154200. View

20.

Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P . A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2000; 276(11):7811-9. DOI: 10.1074/jbc.M008923200. View