The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor

HFE is a class I major histocompatibility complex (MHC)-related protein tha t is mutated in patients with the iron overload disease hereditary hemochro matosis. HFE binds to transferrin receptor (TfR), the receptor used by cell s to obtain iron in the form of diferric transferrin (Fe-Tf). Previous stud ies demonstrated that HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, and that membrane-bound or soluble HFE binding to cell s urface TfR results in a reduction in the affinity of TfR for Fe-Tf. We stud ied the inhibition by soluble HFE of the interaction between soluble TfR an d Fe-Tf using radioactivity-based and biosensor-based assays. The results d emonstrate that HFE inhibits the TfR:Fe-Tf interaction by binding at or nea r the Fe-Tf binding site on TfR, and that the Fe-Tf:TfR:HFE ternary complex consists of one Fe-Tf and one HFE bound to a TfR homodimer. (C) 1999 Acade mic Press.