Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
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.
Lebrón
J A
JA
Division of Biology, California Institute of Technology, Pasadena 91125, USA.
Bennett
M J
MJ
Vaughn
D E
DE
Chirino
A J
AJ
Snow
P M
PM
Mintier
G A
GA
Feder
J N
JN
Bjorkman
P J
PJ
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*
C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin