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J. Biol. Chem., Vol. 282, Issue 51, 36862-36870, December 21, 2007

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HFE Modulates Transferrin Receptor 2 Levels in Hepatoma Cells via Interactions That Differ from Transferrin Receptor 1-HFE Interactions^*

Juxing Chen¹, Maja Chloupková¹, Junwei Gao, Tara L. Chapman-Arvedson, and Caroline A. Enns²

From the Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239 and Amgen, Thousand Oaks, California 91320

Mutations in the transmembrane glycoproteins transferrin receptor 2 (TfR2) and HFE are associated with hereditary hemochromatosis. Interactions between HFE and transferrin receptor 1 (TfR1) have been mapped to the 1- and 2-helices in HFE and to the helical domain of TfR1. Recently, TfR2 was also reported to interact with HFE in transfected mammalian cells. To test whether similar HFE residues are important for both TfR1 and TfR2 binding, a mutant form of HFE (W81AHFE) that has a 5,000-fold lower affinity for TfR1 than HFE was employed. As expected, W81AHFE does not interact with TfR1. However, we found that the same mutation in HFE does not affect the TfR2/HFE interaction. This finding indicates that the TfR2/HFE and TfR1/HFE interactions are distinct. We further observed that, unlike TfR1/HFE, Tf does not compete with HFE for binding to TfR2 and that binding is independent of pH (pH 6–7.5). TfR2-TfR1 and HFE-HLA-B7 chimeras were generated to map the domains of the TfR2/HFE interaction. TfR1 and HLA-B7 were chosen because of their similar overall structures with TfR2 and HFE, respectively. We mapped the interacting domains to the putative stalk and protease-like domains of TfR2 located between residues 104 and 250 and to the 3 domain of HFE, both of which differ from the TfR1/HFE interacting domains. Furthermore, we found that HFE increases TfR2 levels in hepatic cells independent of holo-Tf.

Received for publication, August 13, 2007 , and in revised form, October 22, 2007.

^* This work was supported by National Institutes of Health Grants R01-DK072166 (to C. A. E.) and Amgen (to C. A. E.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: 3181 SW Sam Jackson Park Rd., L215, Portland, OR 97239. Fax: 503-494-4253; E-mail: ennsca{at}ohsu.edu.

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