title: 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena 91125, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Lebrón
authors.forename: M J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: D E
authors.initials: DE
authors.lastname: Vaughn
authors.forename: A J
authors.initials: AJ
authors.lastname: Chirino
authors.forename: P M
authors.initials: PM
authors.lastname: Snow
authors.forename: G A
authors.initials: GA
authors.lastname: Mintier
authors.forename: J N
authors.initials: JN
authors.lastname: Feder
authors.forename: P J
authors.initials: PJ
authors.lastname: Bjorkman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D006680:HLA Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006432:Hemochromatosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008565:Membrane Proteins; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011990:Receptors, Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin