The major-histocompatibility-complex class I–like protein, HFE, which has an ancestral peptide-binding groove that is too narrow for antigen presentation, is also incapable of binding iron.
Newly synthesized HFE binds to beta2-microglobulin,29 an event necessary for its expression on the cell surface and endosomal membranes, where it interacts with transferrin receptor 1 (TFR1), the major receptor for transferrin.
C282Y mutation
By disrupting a disulfide bond in HFE that is critical for its binding to beta2-microglobulin, the C282Y mutation impairs cell-surface expression of HFE and the interaction of HFE with TFR1.
In vitro findings reported in the late 1990s indicated that normal HFE diminished the ligand-binding affinity of TFR1 and that HFE competed with transferrin for iron uptake.
However, more recent studies of cultured macrophages from patients with hereditary hemochromatosis, macrophage cell lines,and cells overexpressing both HFE and beta2-microglobulin suggest that HFE normally facilitates, rather than hinders, TFR1-mediated cellular uptake of transferrin-bound iron.
It now seems that HFE might also bind to other, uncharacterized proteins or exert direct effects on endosomal iron transport.
Pathology
HFE mutations in classic hemochromatosis.
References
Chorney MJ, Yoshida Y, Meyer PN, Yoshida M, Gerhard GS. The enigmatic role of the hemochromatosis protein (HFE) in iron absorption. Trends Mol Med. 2003 Mar;9(3):118-25. PMID: 12657433