Ferroportin Explained

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.^[1] 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.^[2]

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.^[3]

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,^[4] 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.^[5]

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.^{[6] [7]} 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,^[8] and nickel. Ferroportin may also function as a manganese exporter.^[9]

Tissue distribution

Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:^{[10] [11]}

• 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.^[12] 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.^{[13] [14]}

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.^[15]

Role in iron metabolism

Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell.^[16] 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.^[17]

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.^[18]

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 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.^[19]

Further reading

• Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR . 6 . In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations . Blood . 105 . 10 . 4096–4102 . May 2005 . 15692071 . 10.1182/blood-2004-11-4502 . free .
• Pietrangelo A . The ferroportin disease . Blood Cells, Molecules & Diseases . 32 . 1 . 131–138 . 2004 . 14757427 . 10.1016/j.bcmd.2003.08.003 .
• Robson KJ, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, Weatherall DJ, Rochette J . 6 . Recent advances in understanding haemochromatosis: a transition state . Journal of Medical Genetics . 41 . 10 . 721–730 . October 2004 . 15466004 . 1735598 . 10.1136/jmg.2004.020644 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Abboud S, Haile DJ . A novel mammalian iron-regulated protein involved in intracellular iron metabolism . The Journal of Biological Chemistry . 275 . 26 . 19906–19912 . June 2000 . 10747949 . 10.1074/jbc.M000713200 . free .
• Haile DJ . 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 . 10828623 . 10.1159/000015522 . 6098716 .
• McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ . 6 . 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 . 10882071 . 10.1016/S1097-2765(00)80425-6 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P . 6 . A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis . Nature Genetics . 28 . 3 . 213–214 . July 2001 . 11431687 . 10.1038/90038 . 7345473 .
• Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A . 6 . Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene . The Journal of Clinical Investigation . 108 . 4 . 619–623 . August 2001 . 11518736 . 209405 . 10.1172/JCI13468 .
• Press RD . Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin . Molecular Diagnosis . 6 . 4 . 347 . December 2001 . 11774199 . 10.1054/modi.2001.0060347 .
• Lee PL, Gelbart T, West C, Halloran C, Felitti V, Beutler E . 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 . 11783942 . 10.1006/bcmd.2001.0445 .
• Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA . Intestinal expression of genes involved in iron absorption in humans . American Journal of Physiology. Gastrointestinal and Liver Physiology . 282 . 4 . G598–G607 . April 2002 . 11897618 . 10.1152/ajpgi.00371.2001 .
• Thomas C, Oates PS . IEC-6 cells are an appropriate model of intestinal iron absorption in rats . The Journal of Nutrition . 132 . 4 . 680–687 . April 2002 . 11925460 . 10.1093/jn/132.4.680 . free .
• Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN . Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis . Blood . 100 . 2 . 692–694 . July 2002 . 12091366 . 10.1182/blood.v100.2.692 . free .
• Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS . 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 . 12091367 . 10.1182/blood-2001-11-0132 . free .
• Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, Piga A, Mackie PH, Robson KJ, Camaschella C . 6 . A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4 . Blood . 100 . 2 . 733–734 . July 2002 . 12123233 . 10.1182/blood-2002-03-0693 . free .

Notes and References

1. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI . 6 . Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter . Nature . 403 . 6771 . 776–781 . February 2000 . 10693807 . 10.1038/35001596 . 4429026 . 2000Natur.403..776D .
2. Ward DM, Kaplan J . Ferroportin-mediated iron transport: expression and regulation . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1823 . 9 . 1426–1433 . September 2012 . 22440327 . 3718258 . 10.1016/j.bbamcr.2012.03.004 .
3. Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P . Comparative studies of duodenal and macrophage ferroportin proteins . American Journal of Physiology. Gastrointestinal and Liver Physiology . 290 . 1 . G156–G163 . January 2006 . 16081760 . 10.1152/ajpgi.00227.2005 .
4. Web site: SLC11A3 iron transporter [Homo sapiens] ]. Protein - NCBI .
5. Zohn IE, De Domenico I, Pollock A, Ward DM, Goodman JF, Liang X, Sanchez AJ, Niswander L, Kaplan J . 6 . The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease . Blood . 109 . 10 . 4174–4180 . May 2007 . 17289807 . 1885502 . 10.1182/blood-2007-01-066068 .
6. Taniguchi R, Kato HE, Font J, Deshpande CN, Wada M, Ito K, Ishitani R, Jormakka M, Nureki O . 6 . Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin . Nature Communications . 6 . 1 . 8545 . October 2015 . 26461048 . 4633820 . 10.1038/ncomms9545 . 2015NatCo...6.8545T .
7. Deshpande CN, Ruwe TA, Shawki A, Xin V, Vieth KR, Valore EV, Qiao B, Ganz T, Nemeth E, Mackenzie B, Jormakka M . 6 . Calcium is an essential cofactor for metal efflux by the ferroportin transporter family . Nature Communications . 9 . 1 . 3075 . August 2018 . 30082682 . 6079014 . 10.1038/s41467-018-05446-4 . 2018NatCo...9.3075D .
8. Mitchell CJ, Shawki A, Ganz T, Nemeth E, Mackenzie B . Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc . American Journal of Physiology. Cell Physiology . 306 . 5 . C450–C459 . March 2014 . 24304836 . 4042619 . 10.1152/ajpcell.00348.2013 .
9. Madejczyk MS, Ballatori N . The iron transporter ferroportin can also function as a manganese exporter . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1818 . 3 . 651–657 . March 2012 . 22178646 . 5695046 . 10.1016/j.bbamem.2011.12.002 .
10. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC . The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis . Cell Metabolism . 1 . 3 . 191–200 . March 2005 . 16054062 . 10.1016/j.cmet.2005.01.003 . free . Geraldine Pinkus .
11. Delaby C, Pilard N, Puy H, Canonne-Hergaux F . Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression . The Biochemical Journal . 411 . 1 . 123–131 . April 2008 . 18072938 . 10.1042/BJ20071474 .
12. Mao J, McKean DM, Warrier S, Corbin JG, Niswander L, Zohn IE . The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure . Development . 137 . 18 . 3079–3088 . September 2010 . 20702562 . 2926957 . 10.1242/dev.048744 .
13. Felkner MM, Suarez L, Brender J, Scaife B, Hendricks K . Iron status indicators in women with prior neural tube defect-affected pregnancies . Maternal and Child Health Journal . 9 . 4 . 421–428 . December 2005 . 16315101 . 10.1007/s10995-005-0017-3 . 13415844 .
14. Groenen PM, van Rooij IA, Peer PG, Ocké MC, Zielhuis GA, Steegers-Theunissen RP . Low maternal dietary intakes of iron, magnesium, and niacin are associated with spina bifida in the offspring . The Journal of Nutrition . 134 . 6 . 1516–1522 . June 2004 . 15173422 . 10.1093/jn/134.6.1516 . free .
15. Moreno-Navarrete JM, López-Navarro E, Candenas L, Pinto F, Ortega FJ, Sabater-Masdeu M, et al.Ferroportin mRNA is down-regulated in granulosa and cervical cells from infertile women.Fertil Steril. 2017 Jan;107(1):236-242.
16. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J . 6 . Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization . Science . 306 . 5704 . 2090–2093 . December 2004 . 15514116 . 10.1126/science.1104742 . 24035970 . 2004Sci...306.2090N .
17. Ganz T . Hepcidin and iron regulation, 10 years later . Blood . 117 . 17 . 4425–4433 . April 2011 . 21346250 . 3099567 . 10.1182/blood-2011-01-258467 .
18. Sangokoya C, Doss JF, Chi JT . Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin . PLOS Genetics . 9 . 4 . e1003408 . April 2013 . 23593016 . 3616902 . 10.1371/journal.pgen.1003408 . free .
19. Web site: TCDB » SEARCH: 2.A.100.2 members . tcdb.org.