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Iron Regulatory Proteins
The roles of a number of proteins involved in regulating iron metabolism have been recently elucidated.
Iron response elements (IREs)
Iron response elements (IREs)
Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1aqo
PDB ID: 1AQO Addess KJ, Basilion JP, Klausner RD, Rouault TA, Pardi A. Structure and dynamics of the iron responsive element RNA: Implications for binding of the RNA by iron regulatory binding proteins. J Mol Biol. 1997; 274:72-83.
IREs are not actually proteins, but rather are stem-looped sections of mRNA that are involved in the production of ferritin and transferrin receptors. These elements are "responsive" to iron because their binding protein changes its conformation to produce more or less ferritin and transferrin receptors depending on the intracellular iron levels (1). Increased production of ferritin decreases the toxicity of intracellular iron; decreased production of transferrin reduces the concentration of intracellular iron.
An IRE binding protein changes its conformation in response to intracellular iron levels, thus providing a feedback mechanism to regulate intracellular iron (1).
Iron responsive element binding proteins
(IRE BPs)
In response to elevated intracellular iron concentrations, IRE binding proteins change their conformation to promote degradation of transferrin receptor mRNA. Other IRE BPs change their conformation to promote increased ferritin translation.(1)
HepcidinHepcidin
Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1m4e
PDB ID: 1m4e Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002:277;37597-603.
Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Hepcidin may control iron distribution — low hepcidin levels lead to intracellular iron overload, while hepcidin overproduction leads to hypoferremia. Hepcidin regulates cellular iron export by binding to ferroportin (IREG1) on cell surfaces, decreasing the cell's ability to export iron (2). This, in turn, leads to decreased extracellular iron levels.
Hepcidin is secreted by the liver in response to several physiologic states including inflammation, raised body iron, hypoxia, and anemia. In response to these states, a number of signals that have not yet been clearly defined are transmitted to receptor mechanisms such as transferrin receptor 2, IL-6 receptor, HFE, and hemojuvelin, which act on hepatocytes to induce the synthesis and release of hepcidin. There may be interactions between these different signals and receptor mechanisms, and it is not yet known how these are processed to modulate hepcidin. However, it is known that the malfunction of transferrin receptor 2, IL-6 receptor, HFE, and hemojuvelin in different types of hemochromatosis decreases hepcidin output.
Since inflammation and IL-6 are strong stimuli for human hepcidin production, and hepcidin excretion is greatly increased during inflammation in humans, IL-6-induced hepcidin could be the mediator responsible for the iron restriction and inadequate erythropoiesis in anemia of inflammation. The development of hepcidin analogues may therefore have future therapeutic applications (3).
Hephaestin
Located on the basolateral surface of iron-absorptive enterocytes, hephaestin facilitates iron egress from enterocytes, probably by oxidizing iron released through ferroportin (IREG1) (4). This oxidation prepares the iron molecules for loading onto transferrin. Ceruloplasmin (located in the plasma) plays a similar role in macrophages.
HFE proteinHFE protein
Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1a6z
PDB ID: 1a6z Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998:93;111-23.
First identified in humans in 1996, the HFE gene is located on the short arm of chromosome 6 (5). HFE is a 343-amino acid cell surface protein with homology to the major histocompatibility complex (MHC) class I molecules. In hereditary hemochromatosis, a C282Y mutation to the HFE gene causes a structural distortion to the HFE protein that prevents its transport to the cell surface, thereby disabling its ability to downregulate cellular iron uptake. HFE mutations other than C282Y have been identified in a comparatively small number of patients with iron overload. The most common of these is H63D. Compared with HFE knockout mice or C282Y homozygous mice, mice homozygous for H63D have mild increases in parameters of iron status (6).
The role that HFE plays in the physiology of intestinal iron absorption remains uncertain. Two major models have been proposed: 1) HFE exerts its effects on iron homeostasis indirectly, by modulating the expression of hepcidin; and 2) HFE exerts its effects directly, by changing the iron status (and therefore the iron absorptive activity) of intestinal enterocytes. The first model places the primary role of HFE in the liver (hepatocytes and/or Kupffer cells), while the second model places the primary role in the duodenum (crypt cells or villus enterocytes). These models are not mutually exclusive, and it is possible that HFE influences the iron status in each of these cell populations, leading to cell type-specific downstream effects on intestinal iron absorption and body iron distribution (6).
Ceruloplasmin
Ceruloplasmin
Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1kcw
PDB ID: 1kcw Zaitseva I, Zaitsev V, Card G, et al. The X-ray structure of human ceruloplasmin at 3.1 angstrom: Nature of the copper centres. J Biol Inorg Chem. 1996:1;15-23
Located in the plasma, ceruloplasmin is implicated in the release of iron from macrophages and hepatocytes. Ceruloplasmin may be involved in oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric iron), thereby assisting its plasma-borne transport by transferrin, which can only carry iron in the ferric state.
Ceruloplasmin is decreased in hereditary hemochromatosis due to a mutation in the HFE gene (7). Absence of ceruloplasmin (aceruloplasminemia) is a rare genetic disorder that can lead to iron overload.
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References
- (1) Haile DJ, Hentze MW, Rouault TA, et al, Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements. Mol Cell Biol. 1989;9(11):5055-61.
- (2) Nemeth E, Tuttle MS, Powelson J, et al, Hepcidin Regulates Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science. 2004.
- (3) Hugman A. Hepcidin: an important new regulator of iron homeostasis. Clin Lab Haematol. 2006;28(2):75-83.
- (4) Zoller H, Theurl I, Koch RO, et al, Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology. 2003;125(3):746-54.
- (5) Feder JN, Gnirke A, Thomas W, et al, A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399-408.
- (6) Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G590-4.
- (7) Laine F, Ropert M, Lan CL, et al, Serum ceruloplasmin and ferroxidase activity are decreased in HFE C282Y homozygote male iron-overloaded patients. J Hepatol. 2002;36(1):60-5.