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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.
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RED CELLS, IRON, AND ERYTHROPOIESIS
Hepcidin, the hormone of iron metabolism, is bound specifically to  -2-macroglobulin in blood
Gabriela Peslova1,
Jiri Petrak1,2,
Katerina Kuzelova1,
Ivan Hrdy3,
Petr Halada4,
Philip W. Kuchel5,
Shan Soe-Lin6,
Prem Ponka6,
Robert Sutak7,
Erika Becker7,
Michael Li-Hsuan Huang7,
Yohan Suryo Rahmanto7,
Des R. Richardson7,*, and
Daniel Vyoral1,2,7,*
1 Institute of Hematology and Blood Transfusion, Prague, Czech Republic;
2 Charles University in Prague, First Faculty of Medicine, Institute of Pathological Physiology, Prague, Czech Republic;
3 Department of Parasitology, Faculty of Science, Charles University in Prague, Prague, Czech Republic;
4 Institute of Microbiology vvi, Academy of Sciences of the Czech Republic, Prague, Czech Republic;
5 School of Molecular and Microbial Biosciences, University of Sydney, Sydney, Australia;
6 Lady Davis Institute, Montréal, QC; and
7 Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
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 polyacrylamide gel electrophoresis and mass spectrometry. Hepcidin binding to nonactivated 2-M displays high affinity (Kd 177 ± 27 nM), whereas hepcidin binding to albumin was nonspecific and displayed nonsaturable 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. Because 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.
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