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J. Biol. Chem., Vol. 281, Issue 39, 28494-28498, September 29, 2006

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Hereditary Hemochromatosis Protein, HFE, Interaction with Transferrin Receptor 2 Suggests a Molecular Mechanism for Mammalian Iron Sensing^*

Tapasree Goswami¹ and Nancy C. Andrews²

From the Harvard Medical School, Children's Hospital Boston, Division of Hematology/Oncology and Howard Hughes Medical Institute, Boston, Massachusetts 02115-5737

HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis.

Received for publication, July 27, 2006 , and in revised form, August 7, 2006.

^* This work was supported by Grant R01 DK53813 from the National Institutes of Health (to N. C. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship from the Cooley's Anemia Foundation.

² An investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Children's Hospital, Karp Family Research Laboratories, Rm. 8-125, 1, Blackfan Circle, Boston, MA 02115-5737. Tel.: 617-919-2116; Fax: 617-432-3639; E-mail: nancy_andrews{at}hms.harvard.edu.

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