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Blood, 1 January 2006, Vol. 107, No. 1, pp. 328-333. Prepublished online as a Blood First Edition Paper on September 1, 2005; DOI 10.1182/blood-2005-05-2049. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-05-2049v1 107/1/328    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nemeth, E. Articles by Ganz, T. Search for Related Content PubMed PubMed Citation Articles by Nemeth, E. Articles by Ganz, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 23, 2005 Accepted August 22, 2005 The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study Elizabeta Nemeth, Gloria C Preza, Chun-Ling Jung, Jerry Kaplan, Alan J Waring, and Tomas Ganz* Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah, USA Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA * Corresponding author; email: tganz{at}mednet.ucla.edu. Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in mice by the induction of hypoferremia. Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when five N-terminal aa were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin, and did not interfere with ferroportin internalization by native hepcidin. Deletion of two C-terminal aa did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not impact peptide activity in vitro. However, these peptides were less active in vivo, likely due to their decreased stability in circulation. G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. B. Jordan, L. Poppe, M. Haniu, T. Arvedson, R. Syed, V. Li, H. Kohno, H. Kim, P. D. Schnier, T. S. Harvey, et al. Hepcidin Revisited, Disulfide Connectivity, Dynamics, and Structure J. Biol. Chem., September 4, 2009; 284(36): 24155 - 24167. [Abstract] [Full Text] [PDF] P. G. Fraenkel, Y. Gibert, J. L. Holzheimer, V. J. Lattanzi, S. F. Burnett, K. A. Dooley, R. A. Wingert, and L. I. Zon Transferrin-a modulates hepcidin expression in zebrafish embryos Blood, March 19, 2009; 113(12): 2843 - 2850. [Abstract] [Full Text] [PDF] S. A. Browne and D. Reddan Potential role of bone morphogenetic protein (BMP) signalling as a potential therapeutic target for modification of iron balance Nephrol. Dial. Transplant., January 1, 2009; 24(1): 28 - 30. [Full Text] [PDF] R. S. Ajioka, J. D. Phillips, R. B. Weiss, D. M. Dunn, M. W. Smit, S. C. Proll, M. G. Katze, and J. P. Kushner Down-regulation of hepcidin in porphyria cutanea tarda Blood, December 1, 2008; 112(12): 4723 - 4728. [Abstract] [Full Text] [PDF] T. Ganz, G. Olbina, D. Girelli, E. Nemeth, and M. Westerman Immunoassay for human serum hepcidin Blood, November 15, 2008; 112(10): 4292 - 4297. [Abstract] [Full Text] [PDF] N Scamuffa, A Basak, C Lalou, A Wargnier, J Marcinkiewicz, G Siegfried, M Chretien, F Calvo, N G Seidah, and A-M Khatib Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7 Gut, November 1, 2008; 57(11): 1573 - 1582. [Abstract] [Full Text] [PDF] Q. Xu, C.-H. C. Cheng, P. Hu, H. Ye, Z. Chen, L. Cao, L. Chen, Y. Shen, and L. Chen Adaptive Evolution of Hepcidin Genes in Antarctic Notothenioid Fishes Mol. Biol. Evol., June 1, 2008; 25(6): 1099 - 1112. [Abstract] [Full Text] [PDF] E. H.J.M. Kemna, H. Tjalsma, H. L. Willems, and D. W. Swinkels Hepcidin: from discovery to differential diagnosis Haematologica, January 1, 2008; 93(1): 90 - 97. [Abstract] [Full Text] [PDF] T. Ganz Molecular Control of Iron Transport J. Am. Soc. Nephrol., February 1, 2007; 18(2): 394 - 400. [Abstract] [Full Text] [PDF] N. Sheikh, D. S. Batusic, J. Dudas, K. Tron, K. Neubauer, B. Saile, and G. Ramadori Hepcidin and hemojuvelin gene expression in rat liver damage: in vivo and in vitro studies Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G482 - G490. [Abstract] [Full Text] [PDF] D. W. Swinkels, M. C.H. Janssen, J. Bergmans, and J. J.M. Marx Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches Clin. Chem., June 1, 2006; 52(6): 950 - 968. [Abstract] [Full Text] [PDF]

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