Molecular medicine and hemochromatosis: At the crossroads Bruce R. Bacon, Lawrie W. Powell, Paul C. Adams, Thomas F. Kresina, Jay H. Hoofnagle  Gastroenterology  Volume 116, Issue 1, Pages 193-207 (January 1999) DOI: 10.1016/S0016-5085(99)70244-1 Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 1 Hypothetical model of the HFE protein based on homology with MHC molecules. The extracellular component of HFE consists of 3 α domains, 1 of which binds to β2m. The HFE molecule also has a membrane-spanning region and a short cytoplasmic tail. The C282Y mutation substitutes tyrosine for the cysteine involved in the important disulfide bond. The H63D mutation is localed in the α1 domain and may affect tertiary structure of the molecule. (Modified and reprinted with permission.5) Gastroenterology 1999 116, 193-207DOI: (10.1016/S0016-5085(99)70244-1) Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 2 TfR-mediated iron transport. Ferric iron (•) in the circulation binds rapidly to apotransferrin (2). Transferrin with 2 iron molecules (diferric transferrin) will then bind to the TfR on the cellular plasma membrane. The binary complex of TfR with 2 diferric transferrins (in some situations, also bound to a single molecule of HFE) is then internalized in endosomes. With acidification, the ferric ions are released from the complex of TfR-transferrin. Ferric iron is probably reduced to ferrous iron in the acidified endosome and then transported into the cytoplasm via an endosomal membrane iron transporter that is believed to be DMT-1. Cytoplasmic iron is available for metabolic processes or is stored in large ferritin complexes. The TfR with apotransferrin is recycled to the cell membrane where the transferrin molecules are released. (Modified and reprinted with permission.18) Gastroenterology 1999 116, 193-207DOI: (10.1016/S0016-5085(99)70244-1) Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 3 Coordinated regulation of TfR and ferritin by IRPs and IREs found in either the 5' or 3' noncoding regions of iron-responsive genes. In the iron-depleted state, IRPs bind to the IREs on mRNA. Binding of the IRPs to mRNA in the 3' region (as occurs with TfR mRNA) results in stabilization of the RNA and production of more TfR. Binding of IRPs to mRNA in the 5' region (as occurs with ferritin) results in blockage of translation and thus less protein product. The opposite occurs in the iron-repleted state; IRPs do not bind to the IREs on mRNA, and TfR mRNA is degraded rapidly, resulting in less receptor. In contrast, the translation of ferritin from its mRNA is not blocked by the IRP binding to the IRE in the 5' region, and more ferritin is made. (Modified and reprinted with permission.18) Gastroenterology 1999 116, 193-207DOI: (10.1016/S0016-5085(99)70244-1) Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 4 Crystallographic structure of the HFE gene product. HFE (multicolored ribbons) interacts with the TfR (purple oval schematic) at the plasma membrane and lowers the affinity of iron-loaded transferrin (green ribbons with iron shown in red). (Courtesy of Dr. Pamela Bjorkman.) Gastroenterology 1999 116, 193-207DOI: (10.1016/S0016-5085(99)70244-1) Copyright © 1999 American Gastroenterological Association Terms and Conditions

Fig. 5 Hypothesis of regulation of iron absorption by HFE. An intestinal villus is shown with insert enlargements of an enterocyte on the villus tip (where iron is absorbed from the intestine) and a deep crypt cell (where the body iron stores are sensed via transferrin-mediated and HFE-modulated iron transport). Ferric iron is reduced in the intestine to ferrous iron and absorbed via the divalent metal transporter (DMT-1) into the enterocyte on the villus tip. In the enterocyte, iron is oxidized to ferric iron and transported via an as-yet-unidentified basolateral iron transporter into the circulation. In the deep crypt, HFE bound to the TfR modulates the uptake of diferric-transferrin. The level of cytoplasmic iron then acts through the binding of IRPs to IREs on the production of DMT-1 transporter mRNA. Mutations in HFE cause lack of cell surface expression of HFE and dysregulation of TfR-mediated iron uptake and consequent alterations in DMT-1 production. Gastroenterology 1999 116, 193-207DOI: (10.1016/S0016-5085(99)70244-1) Copyright © 1999 American Gastroenterological Association Terms and Conditions