Biology:Ferroportin

Short description: Protein

Generic protein structure example

Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene. Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

After dietary iron is absorbed into the cells of the small intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Fpn also mediates the efflux of iron recycled from macrophages resident in the spleen and liver.

Ferroportin is regulated by hepcidin, a hormone produced by the liver; hepcidin binds to Fpn and limits its iron-efflux activity, thereby reducing iron delivery to the blood plasma. Therefore, the interaction between Fpn and hepcidin controls systemic iron homeostasis.

Structure

Members of the ferroportin family consist of 400-800 amino acid residues, with a highly conserved histidine at residue position 32 (H32), and exhibit 8-12 putative transmembrane domains. Human Fpn consists of 571 amino acid residues. When H32 is mutated in mice, iron transport activity is impaired.

Recent crystal structures generated from a bacterial homologue of ferroportin (from Bdellovibrio bacteriovorus) revealed that the Fpn structure resembles that of major facilitator superfamily (MFS) transporters. The prospective substrate binding site is located at the interface between the N-terminal and C-terminal halves of the protein, and is alternately accessible from either side of the cell membrane, consistent with MFS transporters.

Function

Ferroportin-mediated iron efflux is calcium-activated; studies of human Fpn expressed in Xenopus laevis oocytes demonstrated that calcium is a required cofactor for Fpn, but that Fpn does not transport calcium. Thus, Fpn does not function as an iron/calcium antiporter. The thermodynamic driving force for Fpn remains unknown.

In addition to iron, human ferroportin has been shown to transport cobalt, zinc, and nickel. Ferroportin may also function as a manganese exporter.

Tissue distribution

Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:

• Enterocytes in the duodenum
• Hepatocytes
• Macrophages of the reticuloendothelial system
• Adipocytes

Role in development

Ferroportin-1 plays an important role in neural tube closure and forebrain patterning. Mouse embryos lacking the Slc40a1 gene are aborted before gastrulation occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development. Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5. Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.

A study examining the consequences of several different mutations of the Slc40a1 mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others. Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.

Role in fertility

It is known that ferroportin (SLC40A1) gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in granulosa cells. What's more, low expression of ferroportin is also associated with infertility when some features like age and smoking habits are considered. It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status.

Role in iron metabolism

Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell. This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. Hepcidin is synthesized in response to various cytokines, as described in the Hepcidin article, as well as in this article by Ganz.

Ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation and increasing intracellular iron and ferritin concentrations. The ferroportin translation is also down regulated post-transcriptionally by the micro RNA miR-485-3p, which is produced in response to iron deficiency.

Clinical significance

Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as Hemochromatosis type 4 or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis.

Protein family

Ferroportin
Identifiers
Symbol	FPN
Pfam	PF06963
InterPro	IPR009716
TCDB	2.A.100
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Ferroportin is part of the ferroportin (Fpn) family. Members of the family are found across eukaryotes in animals and plants as well as in Proteobacteria, a group of bacteria.

Further reading

• "In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations". Blood 105 (10): 4096–4102. May 2005. doi:10.1182/blood-2004-11-4502. PMID 15692071. 
• "The ferroportin disease". Blood Cells, Molecules & Diseases 32 (1): 131–138. 2004. doi:10.1016/j.bcmd.2003.08.003. PMID 14757427. 
• "Recent advances in understanding haemochromatosis: a transition state". Journal of Medical Genetics 41 (10): 721–730. October 2004. doi:10.1136/jmg.2004.020644. PMID 15466004. 
• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–174. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–156. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "A novel mammalian iron-regulated protein involved in intracellular iron metabolism". The Journal of Biological Chemistry 275 (26): 19906–19912. June 2000. doi:10.1074/jbc.M000713200. PMID 10747949. 
• "Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization". Cytogenetics and Cell Genetics 88 (3–4): 328–329. 2000. doi:10.1159/000015522. PMID 10828623. 
• "A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation". Molecular Cell 5 (2): 299–309. February 2000. doi:10.1016/S1097-2765(00)80425-6. PMID 10882071. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–1795. November 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis". Nature Genetics 28 (3): 213–214. July 2001. doi:10.1038/90038. PMID 11431687. 
• "Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene". The Journal of Clinical Investigation 108 (4): 619–623. August 2001. doi:10.1172/JCI13468. PMID 11518736. 
• "Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin". Molecular Diagnosis 6 (4): 347. December 2001. doi:10.1054/modi.2001.0060347. PMID 11774199. 
• "A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin". Blood Cells, Molecules & Diseases 27 (5): 783–802. 2001. doi:10.1006/bcmd.2001.0445. PMID 11783942. 
• "Intestinal expression of genes involved in iron absorption in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology 282 (4): G598–G607. April 2002. doi:10.1152/ajpgi.00371.2001. PMID 11897618. 
• "IEC-6 cells are an appropriate model of intestinal iron absorption in rats". The Journal of Nutrition 132 (4): 680–687. April 2002. doi:10.1093/jn/132.4.680. PMID 11925460. 
• "Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis". Blood 100 (2): 692–694. July 2002. doi:10.1182/blood.v100.2.692. PMID 12091366. 
• "Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3)". Blood 100 (2): 695–697. July 2002. doi:10.1182/blood-2001-11-0132. PMID 12091367. 
• "A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4". Blood 100 (2): 733–734. July 2002. doi:10.1182/blood-2002-03-0693. PMID 12123233. 

External links

• ferroportin1+protein at the US National Library of Medicine Medical Subject Headings (MeSH)

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