Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor

Abstract

HFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 A crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex.

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.…”

Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes

“…Both L46W and D129N patients' families were not available to be studied, so it was not possible to observe a familiar segregation associated to the iron overload phenotype. The L46W mutation is localized near the flexible HFE α1 domain loop Q40-S45, which interacts with helix 1 of the transferrin receptor 1 (TfR1) helical domain [32,33]. On the other hand, the D129N mutation modifies a residue located in HFE α2 domain which interacts with helix 2 of TfR1.…”

“…1 Sequencing results showing the mutations found in the HFE, TFR2 and HJV genes although his father is a compound heterozygous for Y230F and H63D, he presents normal iron parameters (Table 1). Y230F alters a residue positioned on a β-strand of the α3 domain which binds to β2-microglobulin [32,33]. However, the Y230 position is originally occupied by a phenylalanine in some species (Fig.…”

Immunological study of complex formation between soluble transferrin receptor and transferrin

“…A tryptic fragment of placental TfR starting from the 121-amino acid residue was assumed to be a dimer according to its molecular mass and Stokes radius calculated from FPLC gel filtration experiments [15]. Analogous 121-to 760-amino acid residue fragment produced by recombinant techniques were also assumed to be dimers according to FPLC gel filtration, which also made it possible to suggest that this fragment forms a 2:2 quadruple complex with transferrin [16]. A dimeric form of sTfR in the blood was also proposed [17,18].…”