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 Å 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.
Additional Information
© 1998 Cell Press. Received 16 January 1998, Revised 26 February 1998. We thank T. L. Chapman for performing the acid elutions, I. Nangiana and D. Penny for assistance with protein expression, the Caltech PPMAL for peptide and protein analyses, Drs. C. Ogata and M. Soltis for assistance with synchrotron data collection, Drs. I. A. Wilson and B. Segelke for providing CD1 coordinates prior to PDB release and helpful discussions regarding groove surface area calculations, Dr. P. Poon for performing the analytical ultracentrifugation studies of TfR, and Dr. L. Sánchez for critical reading of the manuscript. M. J. B. was supported by a grant from the Cancer Research Institute, and J. A. L. was supported by a FORD fellowship. Atomic coordinates for HFE have been deposited with the Protein Data Bank.Additional details
- Eprint ID
- 75778
- DOI
- 10.1016/S0092-8674(00)81151-4
- Resolver ID
- CaltechAUTHORS:20170406-075856965
- Cancer Research Institute
- Ford Foundation
- Created
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2017-04-06Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field