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The catalytic center of ferritin regulates iron storage via Fe(II)-Fe(III) displacement

Nature Chemical Biology volume 8, pages 941–948 (2012)Cite this article

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A Corrigendum to this article was published on 20 May 2013

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Abstract

A conserved iron-binding site, the ferroxidase center, regulates the vital iron storage role of the ubiquitous protein ferritin in iron metabolism. It is commonly thought that two Fe(II) simultaneously bind the ferroxidase center and that the oxidized Fe(III)-O(H)-Fe(III) product spontaneously enters the cavity of ferritin as a unit. In contrast, in some bacterioferritins and in archaeal ferritins a persistent di-iron prosthetic group in this center is believed to mediate catalysis of core formation. Using a combination of binding experiments and isotopically labeled 57Fe(II), we studied two systems in comparison: the ferritin from the hyperthermophilic archaeal anaerobe Pyrococcus furiosus (PfFtn) and the eukaryotic human H ferritin (HuHF). The results do not support either of the two paradigmatic models; instead they suggest a unifying mechanism in which the Fe(III)-O-Fe(III) unit resides in the ferroxidase center until it is sequentially displaced by Fe(II).

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Figure 1: The conserved structure of 24-meric ferritin and its active center that catalyzes oxidation of Fe(II).
Figure 2: Presence of a conserved gateway to the ferroxidase center.
Figure 3: Transferrin scavenges Fe(III) from the ferroxidase center.
Figure 4: The fate of Fe(III) product in the ferroxidase center upon addition and oxidation of Fe(II).
Figure 5: EPR monitoring of the state of the Fe(III) product in the ferroxidase center after anaerobic addition of Fe(II).
Figure 6: Schematic representation of a model for the distribution of Fe(III) and Fe(II) after anaerobic addition of Fe(II) to ferritin containing two Fe(III) per subunit.

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  • 19 April 2013

    In the version of this article initially published, the units (kJ mol−1) associated with the ΔH values reported in Table 1 were inadvertently omitted. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The construct for production of recombinant HuHF was kindly provided by P. Arosio (University of Brescia). We thank L. van der Weel for assistance with expression of ferritin, M.J.F. Strampraad for technical assistance, D. Sordi for her assistance with the E129R mutation, M.M. Kabir for assistance with kinetic measurements and B. Mienert for Mössbauer measurements. This work was financially supported by a research grant from the Dutch National Research School Combination–Catalysis Controlled by Chemical Design (NRSC-C).

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Authors and Affiliations

  1. Department of Biotechnology, Delft University of Technology, Delft, The Netherlands

    Kourosh Honarmand Ebrahimi, Peter-Leon Hagedoorn & Wilfred R Hagen

  2. Max-Planck-Institut für Bioanorganische Chemie, Mülheim an der Ruhr, Germany

    Eckhard Bill

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  1. Kourosh Honarmand Ebrahimi
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Contributions

K.H.E., P.-L.H. and W.R.H. designed the research; K.H.E. performed the experiments; K.H.E., P.-L.H., E.B. and W.R.H. analyzed the data and wrote the manuscript.

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Correspondence to Wilfred R Hagen.

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Honarmand Ebrahimi, K., Bill, E., Hagedoorn, PL. et al. The catalytic center of ferritin regulates iron storage via Fe(II)-Fe(III) displacement. Nat Chem Biol 8, 941–948 (2012). https://doi.org/10.1038/nchembio.1071

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