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The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding

Feder, John N. and Penny, David M. and Irrinki, Alivelu and Lee, Vince K. and Lebrón, José A. and Watson, Nicole and Tsuchihashi, Zenta and Sigal, Elliot and Bjorkman, Pamela J. and Schatzman, Randall C. (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proceedings of the National Academy of Sciences of the United States of America, 95 (4). pp. 1472-1477. ISSN 0027-8424. PMCID PMC19050. http://resolver.caltech.edu/CaltechAUTHORS:20141126-133454919

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Abstract

We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis called HFE. The gene product, a member of the major histocompatibility complex class I-like family, was found to have a mutation, Cys-282 → Tyr (C282Y), in 85% of patient chromosomes. This mutation eliminates the ability of HFE to associate with β2-microglobulin (β_2m) and prevents cell-surface expression. A second mutation that has no effect on β2m association, H63D, was found in eight out of nine patients heterozygous for the C282Y mutant. In this report, we demonstrate in cultured 293 cells overexpressing wild-type or mutant HFE proteins that both the wild-type and H63D HFE proteins form stable complexes with the transferrin receptor (TfR). The C282Y mutation nearly completely prevents the association of the mutant HFE protein with the TfR. Studies on cell-associated transferrin at 37°C suggest that the overexpressed wild-type HFE protein decreases the affinity of the TfR for transferrin. The overexpressed H63D protein does not have this effect, providing the first direct evidence for a functional consequence of the H63D mutation. Addition of soluble wild-type HFE/β_2m heterodimers to cultured cells also decreased the apparent affinity of the TfR for its ligand under steady-state conditions, both in 293 cells and in HeLa cells. Furthermore, at 4°C, the added soluble complex of HFE/β2m inhibited binding of transferrin to HeLa cell TfR in a concentration-dependent manner. Scatchard plots of these data indicate that the added heterodimer substantially reduced the affinity of TfR for transferrin. These results establish a molecular link between HFE and a key protein involved in iron transport, the TfR, and raise the possibility that alterations in this regulatory mechanism may play a role in the pathogenesis of hereditary hemochromatosis.


Item Type:Article
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URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.95.4.1472DOIArticle
http://www.pnas.org/content/95/4/1472PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC19050/PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 1998 The National Academy of Sciences. Communicated by William S. Sly, Saint Louis University School of Medicine, St. Louis, MO, December 19, 1997 (received for review October 14, 1997). We thank C. Enns, A. Grinke, and W. Thomas for scientific discussion and critical reading of the manuscript, and N. Moeller for her assistance in tissue culture. J.A.L. was supported by a FORD fellowship. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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Funding AgencyGrant Number
Ford FoundationUNSPECIFIED
PubMed Central ID:PMC19050
Record Number:CaltechAUTHORS:20141126-133454919
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20141126-133454919
Official Citation:Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebrón, J. A., Watson, N., . . . Schatzman, R. C. (1998). The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proceedings of the National Academy of Sciences, 95(4), 1472-1477.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52185
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:27 Nov 2014 01:49
Last Modified:20 Jul 2017 20:18

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