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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6225-6236. Prepublished online as a Blood First Edition Paper on April 20, 2009; DOI 10.1182/blood-2009-01-201590. This Article Full Text (PDF) All Versions of this Article: blood-2009-01-201590v1 113/24/6225    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Peslova, G. Articles by Vyoral, D. Search for Related Content PubMed PubMed Citation Articles by Peslova, G. Articles by Vyoral, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 26, 2009 Accepted April 13, 2009 Hepcidin, the hormone of iron metabolism, is bound specifically to -2-macroglobulin in blood Gabriela Peslova, Jiri Petrak, Katerina Kuzelova, Ivan Hrdy, Petr Halada, Philip W. Kuchel, Shan Soe-Lin, Prem Ponka, Robert Sutak, Erika Becker, Michael Li-Hsuan Huang, Yohan Suryo Rahmanto, Des R. Richardson, and Daniel Vyoral* Institute of Hematology and Blood Transfusion, Prague, Czech Republic Charles University in Prague, First Faculty of Medicine, Institute of Pathological Physiology, Prague, Czech Republic Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, Australia Lady Davis Institute, Montreal, Quebec, Canada Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW, Australia * Corresponding author; email: daniel.vyoral{at}uhkt.cz. Hepcidin is a major regulator of iron metabolism. Hepcidin-based therapeutics/diagnostics could play roles in hematology in the future, and thus, hepcidin transport is crucial to understand. In this study, we identify 2-macroglobulin (2-M) as the specific hepcidin-binding molecule in blood. Interaction of 125I-hepcidin with 2-M was identified using fractionation of plasma proteins followed by native gradient PAGE and mass spectrometry. Hepcidin-binding to non-activated 2-M displays high affinity (Kd 177 ± 27 nM), whereas hepcidin binding to albumin was non-specific and displayed non-saturable kinetics. Surprisingly, the interaction of hepcidin with activated 2-M exhibited a classical sigmoidal binding curve demonstrating cooperative binding of 4 high affinity (Kd 0.3 µM) hepcidin-binding sites. This property probably enables efficient sequestration of hepcidin and its subsequent release or inactivation that may be important for its effector functions. Since 2-M rapidly targets ligands to cells via receptor-mediated endocytosis, the binding of hepcidin to 2-M may influence its functions. In fact, the 2-M-hepcidin complex decreased ferroportin expression in J774 cells more effectively than hepcidin alone. The demonstration that 2-M is the hepcidin transporter could lead to better understanding of hepcidin physiology, methods for its sensitive measurement and the development of novel drugs for the treatment of iron-related diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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