Crossref journal-article
American Society of Hematology
Blood (234)
Abstract

Abstract Ferroportin (Fpn) (IREG1, SLC40A1, MTP1) is an iron transporter, and mutations in Fpn result in a genetically dominant form of iron overload disease. Previously, we demonstrated that Fpn is a multimer and that mutations in Fpn are dominant negative. Other studies have suggested that Fpn is not a multimer and that overexpression or epitope tags might affect the localization, topology, or multimerization of Fpn. We generated wild-type Fpn with 3 different epitopes, GFP, FLAG, and c-myc, and expressed these constructs in cultured cells. Co-expression of any 2 different epitope-tagged proteins in the same cell resulted in their quantitative coimmunoprecipitation. Treatment of Fpn-GFP/Fpn-FLAG–expressing cells with crosslinking reagents resulted in the crosslinking of Fpn-GFP and Fpn-FLAG. Western analysis of rat glioma C6 cells or mouse bone marrow macrophages exposed to crosslinking reagents showed that endogenous Fpn is a dimer. These results support the hypothesis that the dominant inheritance of Fpn–iron overload disease is due to the dominant-negative effects of mutant Fpn proteins.

Bibliography

De Domenico, I., Ward, D. M., Musci, G., & Kaplan, J. (2006). Evidence for the multimeric structure of ferroportin. Blood, 109(5), 2205–2209.

Authors 4
  1. Ivana De Domenico (first)
  2. Diane McVey Ward (additional)
  3. Giovanni Musci (additional)
  4. Jerry Kaplan (additional)
References 20 Referenced 53
  1. Ganz T and Nemeth E. Iron imports, IV: hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol2006; 290:G199–G203. (10.1152/ajpgi.00412.2005)
  2. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science2004; 306:2090–2093. (10.1126/science.1104742)
  3. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest2001; 108:619–623. (10.1172/JCI200113468)
  4. De Domenico I, Ward DM, Nemeth E, et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A2005; 102:8955–8960. (10.1073/pnas.0503804102)
  5. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood2005; 105:4096–4102. (10.1182/blood-2004-11-4502)
  6. Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood2005; 106:1092–1097. (10.1182/blood-2005-02-0561)
  7. Yang F, Liu XB, Quinones M, Melby PC, Ghio A, Haile DJ. Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem2002; 277:39786–39791. (10.1074/jbc.M201485200)
  8. Pietrangelo A. Non-HFE hemochromatosis. Semin Liver Dis2005; 25:450–460. (10.1055/s-2005-923316)
  9. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab2005; 1:191–200. (10.1016/j.cmet.2005.01.003)
  10. Goncalves AS, Muzeau F, Blaybel R, et al. Wild-type and mutant ferroportins do not form oligomers in transfected cells. Biochem J2006; 396:265–275. (10.1042/BJ20051682)
  11. Pignatti E, Mascheroni L, Sabelli M, Barelli S, Biffo S, Pietrangelo A. Ferroportin is a monomer in vivo in mice. Blood Cells Mol Dis2006; 36:26–32. (10.1016/j.bcmd.2005.11.001)
  12. Liu XB, Yang F, Haile DJ. Functional consequences of ferroportin 1 mutations. Blood Cells Mol Dis2005; 35:33–46. (10.1016/j.bcmd.2005.04.005)
  13. Jeong SY and David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem2003; 278:27144–27148. (10.1074/jbc.M301988200)
  14. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood2005; 106:3979–3984. (10.1182/blood-2005-06-2398)
  15. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis2004; 32:131–138. (10.1016/j.bcmd.2003.08.003)
  16. De Domenico I, McVey Ward D, Nemeth E, et al. Molecular and clinical correlates in iron overload associated with mutations in ferroportin. Haematologica2006; 91:1092–1095.
  17. Liu W, Shimomura S, Imanishi H, et al. Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene. Intern Med2005; 44:285–289. (10.2169/internalmedicine.44.285)
  18. Mok H, Jelinek J, Pai S, et al. Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. Development2004; 131:1859–1868. (10.1242/dev.01081)
  19. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell2004; 117:285–297. (10.1016/S0092-8674(04)00343-5)
  20. McGregor JA, Shayeghi M, Vulpe CD, et al. Impaired iron transport activity of ferroportin 1 in hereditary iron overload. J Membr Biol2005; 206:3–7. (10.1007/s00232-005-0768-1)
Dates
Type When
Created 18 years, 9 months ago (Nov. 2, 2006, 3:26 a.m.)
Deposited 5 years, 9 months ago (Nov. 17, 2019, 2:33 p.m.)
Indexed 4 months, 1 week ago (April 22, 2025, 4:09 a.m.)
Issued 18 years, 10 months ago (Oct. 31, 2006)
Published 18 years, 10 months ago (Oct. 31, 2006)
Published Online 18 years, 10 months ago (Oct. 31, 2006)
Published Print 18 years, 5 months ago (March 1, 2007)
Funders 0

None

@article{De_Domenico_2006, title={Evidence for the multimeric structure of ferroportin}, volume={109}, ISSN={1528-0020}, url={http://dx.doi.org/10.1182/blood-2006-06-032516}, DOI={10.1182/blood-2006-06-032516}, number={5}, journal={Blood}, publisher={American Society of Hematology}, author={De Domenico, Ivana and Ward, Diane McVey and Musci, Giovanni and Kaplan, Jerry}, year={2006}, month=oct, pages={2205–2209} }