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Structural Mechanism Shows How Transferrin Receptor Binds Multiple Ligands and Sheds Light on a Hereditary Iron Disease

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While the molecular pathway that mediates cellular intake of iron through the TfR is known, it was not clear just how TfR assists in iron release to the cell and how it binds HFE and transferrin... Bjorkman's lab, which had previously solved the structures of both HFE and HFE bound to the TfR, used their structural information to investigate how the proteins interact, which amino acid residues are required for binding, whether the two ligands bind differently to the receptor, and how HFE binding affects transferrin binding... They found that Fe-Tf and HFE occupy the same or an overlapping site on the receptor, but since transferrin is much larger than the HFE protein, it appeared that transferrin could also interact with other parts of TfR... In this study, Bjorkman and colleagues expanded their library of TfR mutants to clarify the transferrin binding signature on TfR and to see how the TfR mutations affect the way apo-Tf and Fe-Tf interact with the receptor... Four of these residues are essential for transferrin binding and are conserved in all known TfR DNA sequences... Since residues that didn't have much impact are not conserved, the scientists say the results are likely to describe transferrin–TfR interactions for other species as well... As expected, the most critical residues required for transferrin binding fall within the receptor's helical domain and have significant physical overlap with residues required for HFE binding; though some residues that are required for apo-Tf binding do not affect Fe-Tf binding... Bjorkman et al. also identify additional residues in another domain on TfR (called the protease-like domain) that support Fe-Tf but not apo-Tf binding, confirming that the receptor binding footprints of the two metal-binding states of transferrin are indeed different... By suggesting a mechanism through which TfR binding regulates iron release, this structural model of the transferrin–TfR complex will bolster efforts to elucidate the molecular details of this process... Confirmation that transferrin and HFE do indeed compete for docking privileges reveals a possible role for HFE in maintaining iron homeostasis and will provide valuable insights into the dysregulation that leads to the warehousing of iron and resulting tissue and organ damage associated with hemochromatosis.

No MeSH data available.


Ribbon diagram of transferrin receptor homodimer
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pbio.0000029-g001: Ribbon diagram of transferrin receptor homodimer


Structural Mechanism Shows How Transferrin Receptor Binds Multiple Ligands and Sheds Light on a Hereditary Iron Disease
Ribbon diagram of transferrin receptor homodimer
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC300675&req=5

pbio.0000029-g001: Ribbon diagram of transferrin receptor homodimer

View Article: PubMed Central

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

While the molecular pathway that mediates cellular intake of iron through the TfR is known, it was not clear just how TfR assists in iron release to the cell and how it binds HFE and transferrin... Bjorkman's lab, which had previously solved the structures of both HFE and HFE bound to the TfR, used their structural information to investigate how the proteins interact, which amino acid residues are required for binding, whether the two ligands bind differently to the receptor, and how HFE binding affects transferrin binding... They found that Fe-Tf and HFE occupy the same or an overlapping site on the receptor, but since transferrin is much larger than the HFE protein, it appeared that transferrin could also interact with other parts of TfR... In this study, Bjorkman and colleagues expanded their library of TfR mutants to clarify the transferrin binding signature on TfR and to see how the TfR mutations affect the way apo-Tf and Fe-Tf interact with the receptor... Four of these residues are essential for transferrin binding and are conserved in all known TfR DNA sequences... Since residues that didn't have much impact are not conserved, the scientists say the results are likely to describe transferrin–TfR interactions for other species as well... As expected, the most critical residues required for transferrin binding fall within the receptor's helical domain and have significant physical overlap with residues required for HFE binding; though some residues that are required for apo-Tf binding do not affect Fe-Tf binding... Bjorkman et al. also identify additional residues in another domain on TfR (called the protease-like domain) that support Fe-Tf but not apo-Tf binding, confirming that the receptor binding footprints of the two metal-binding states of transferrin are indeed different... By suggesting a mechanism through which TfR binding regulates iron release, this structural model of the transferrin–TfR complex will bolster efforts to elucidate the molecular details of this process... Confirmation that transferrin and HFE do indeed compete for docking privileges reveals a possible role for HFE in maintaining iron homeostasis and will provide valuable insights into the dysregulation that leads to the warehousing of iron and resulting tissue and organ damage associated with hemochromatosis.

No MeSH data available.