3D Structure of HFE

CPK Color Scheme
C O N P S



HFE is homologous to class I MHC proteins and regulates iron concentration in cells. When mutated, HFE causes the recessive disease hemochromatosis. If hemochromatosis is not treated with blood letting, it can lead to heart, liver, or pancreas damage and premature death (Davies and Enns, 2004). See the previous two pages on HFE structure-function relationship and HFE orthologs to review more detailed information on the protein.

Now, see below for an interactive Chime tutorial on the structure and function of HFE!


Reset the view of HFE. Here you see HFE as a dimer, which is an artifact of crystallization. In the body, HFE is expressed as a monomer, which I shall depict and discuss for the rest of the tutorial. Click here.

HFE is made up of three alpha domains: Alpha-1 and alpha-2, the extracellular domains, are on the right and left half, respectively, of the green portion of the protein. Together, the first two alpha domains consist of two alpha helices on top of eight beta pleated sheets. The helices and sheets are anti parallel. Alpha-3, the transmembrane domain, is the blue portion. Alpha-3 forms a heterodimer with beta2m (cyan portion), beta-2-microglobulin protein. Click here.

Here is a cluster of histidines and a nearby tyrosine. This conformation resembles that of iron binding sites in some other proteins. Data suggest that in HFE these residues may bind iron only at certain pHs, and thus act as a pH-dependent activation switch. Click here. For a closer look, zoom in here.

Most class I MHC proteins have a functional peptide binding groove, which HFE lacks. In HFE, the groove between the alpha-1 helix and the alpha-2 helix is unusually narrow. As a result, amino acids that form pockets in class I MHC molecules are buried. Also, a bound peptide would create steric clashes with a total of ten residues in the HFE alpha-1 and alpha-2 helices. To view the buried amino acids, click here. To view the amino acids that would clash with a peptide, click here.

Here is the disulfide bond between C260 and C203 that is disrupted in the C260Y mutation. This mutation is the most common hemochromatosis mutation. Click here. For a close up, click here.

Highlight H41 and A73. A salt bridge forms between these two amino acids. When the H41A mutation occurs, it causes local rearrangement in the protein. When heterozygous with the C260Y phenotype, this mutation can lead to hemochromatosis. Click here.


REFERENCES

Davies PS, Enns CA. 2004. Expression of the Hereditary Hemochromatosis Protein HFE Increases Ferritin Levels by Inhibiting Iron Export in HT29 Cells. Journal of Biological Chemistry 279 (24): 25085-25092.

Lebron JA, et al. 1998. Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor. Cell 93: 111-123.