Hepcidin, the hormone of iron metabolism, is bound specifically to α-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, Daniel Vyoral

Research output: Contribution to journalArticle

Abstract

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 α2-macroglobulin (α2-M) as the specific hepcidin-binding molecule in blood. Interaction of 125I-hepcidin with α2-M was identified using fractionation of plasma proteins followed by native gradient polyacrylamide gel electrophoresis and mass spectrometry. Hepcidin binding to nonactivated α2-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 α2-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 α2-M rapidly targets ligands to cells via receptor-mediated endocytosis, the binding of hepcidin to α2-M may influence its functions. In fact, the α2-M-hepcidin complex decreased ferroportin expression in J774 cells more effectively than hepcidin alone. The demonstration that α2-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.

Original languageEnglish (US)
Pages (from-to)6225-6236
Number of pages12
JournalBlood
Volume113
Issue number24
DOIs
Publication statusPublished - Nov 20 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., ... Vyoral, D. (2009). Hepcidin, the hormone of iron metabolism, is bound specifically to α-2-macroglobulin in blood. Blood, 113(24), 6225-6236. https://doi.org/10.1182/blood-2009-01-201590