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

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 3 Tyr (C282Y), in 85% of patient chromosomes. This mutation eliminates the ability of HFE to associate with ␤ 2 -microglobulin (␤ 2 m) and prevents cellsurface expression. A second mutation that has no effect on ␤ 2 m 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 HFE͞␤ 2 m 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 HFE͞␤ 2 m 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.

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

“…This observation may give us some insight into the mechanism whereby the lymphocytes could contribute to the regulation of iron metabolism. The postulated influence of the H63D mutation on the regulation of the transferrin receptor-mediated iron uptake (Feder et al 1998) occurring in a specific MHC class I background could contribute both to the setting of CD8 + numbers and to the regulation of transferrin iron loading. Activated T lymphocytes express transferrin receptors (Pattanapanyasat and Hoy 1991).…”

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

“…The discovery of HFE [12], a protein that plays a key role in the regulation of body iron, and of HFE gene mutations causing genetic hemochromatosis has opened up new perspectives in the study of the relationship between iron and AD. The known function of HFE is to complex the transferrin receptor on the cell membrane and lowering its affinity for ironbound transferrin [13]. Hemochromatosis is the most common inherited monogenic disorder in people of European descent.…”

The major histocompatibility complex-encoded class I-like HFE abrogates endocytosis of transferrin receptor by inducing receptor phosphorylation

“…5 A recent demonstration of the association between HFE molecule and transferrin receptor (TfR) provides critical insights into the roles of HFE in iron homeostasis. [6][7][8][9] Because the levels of TfR expression are functionally linked to the requirements of the cells for iron, TfR plays an essential role in cellular iron metabolism. [10][11][12][13] 8 May 2000 ment and an abnormal iron homeostasis.…”

“…11 It has been reported that by associating with TfR, HFE appears to be able to reduce the affinity of TfR for its ligand. 9,15 However, it is important to note that TfR-Tf complexes undergo rapid recycling and that the concentration of diferric Tf in blood is ෂ5 m, a value that greatly exceeds the K D of Tf for TfR. 11 In this regard, it is unlikely that the effects of HFE on TfR function are simply attributed to a reduction of Tf affinity.…”