Abstract
HFE is related to major histocompatibility complex (MHC) class I proteins and is mutated in the iron-overload disease hereditary haemochromatosis. HFE binds to the transferrin receptor (TfR), a receptor by which cells acquire iron-loaded transferrin. The 2.8 Å crystal structure of a complex between the extracellular portions of HFE and TfR shows two HFE molecules which grasp each side of a twofold symmetric TfR dimer. On a cell membrane containing both proteins, HFE would ‘lie down’ parallel to the membrane, such that the HFE helices that delineate the counterpart of the MHC peptide-binding groove make extensive contacts with helices in the TfR dimerization domain. The structures of TfR alone and complexed with HFE differ in their domain arrangement and dimer interfaces, providing a mechanism for communicating binding events between TfR chains. The HFE–TfR complex suggests a binding site for transferrin on TfR and sheds light upon the function of HFE in regulating iron homeostasis.
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Acknowledgements
We thank C. M. Lawrence and S. C. Harrison for sharing structural information and coordinates before publication; Z. A. Hamburger for assistance with synchrotron data collection; A. Cohen and M. Soltis for synchrotron support; P. M. Snow and I. Nangiana for expression of TfR; S. Jones for assistance with interface analyses; and A. J. Chirino, C. Enns and J. N. Feder for helpful discussions. M.J.B. was supported by a Cancer Research Institute Postdoctoral fellowship.
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Bennett, M., Lebrón, J. & Bjorkman, P. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403, 46–53 (2000). https://doi.org/10.1038/47417
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DOI: https://doi.org/10.1038/47417
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