Ferroportin

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.^[5] 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.^[6]

SLC40A1
Identifiers
Aliases	SLC40A1, IREG1, MST079, MSTP079, solute carrier family 40 member 1, MTP1, SLC11A3, FPN1, HFE4
External IDs	OMIM: 604653 MGI: 1315204 HomoloGene: 40959 GeneCards: SLC40A1
Gene location (Human) Chr. Chromosome 2 (human)^[1] Band 2q32.2 Start 189,560,590 bp^[1] End 189,583,758 bp^[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)^[2] Band 1|1 C1.1 Start 45,947,228 bp^[2] End 45,965,683 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pancreatic ductal cell jejunal mucosa germinal epithelium spongy bone palpebral conjunctiva superficial temporal artery duodenum caput epididymis parietal pleura gallbladder Top expressed in medullary collecting duct duodenum spleen left colon liver ileum yolk sac left lobe of liver extraocular muscle ureter More reference expression data BioGPS n/a
Gene ontology Molecular function ferrous iron transmembrane transporter activity iron ion transmembrane transporter activity peptide hormone binding protein binding identical protein binding Cellular component cytoplasm integral component of membrane membrane synaptic vesicle plasma membrane integral component of plasma membrane intracellular anatomical structure basolateral plasma membrane nucleoplasm cytosol Biological process iron ion transmembrane transport lymphocyte homeostasis spleen trabecula formation iron ion homeostasis negative regulation of apoptotic process ion transport spleen development multicellular organismal iron ion homeostasis iron ion transport endothelium development iron ion export across plasma membrane positive regulation of transcription by RNA polymerase II cellular iron ion homeostasis regulation of transcription from RNA polymerase II promoter in response to iron Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 30061 53945 Ensembl ENSG00000138449 ENSMUSG00000025993 UniProt Q9NP59 Q9JHI9 RefSeq (mRNA) NM_014585 NM_016917 RefSeq (protein) NP_055400 NP_058613 Location (UCSC) Chr 2: 189.56 – 189.58 Mb Chr 1: 45.95 – 45.97 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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.^[8] Therefore, the interaction between Fpn and hepcidin controls systemic iron homeostasis.

Structure

Members of the ferroportin family consist of 400-800 amino acid residues,^[9] 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.^[9] When H32 is mutated in mice, iron transport activity is impaired.^[10]

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.^[11][12] 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,^[12] 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.^[12] 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,^[13] and nickel.^[12] Ferroportin may also function as a manganese exporter.^[14]

Tissue distribution

Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:^[15][16]

• 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.^[17] 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.^[15] Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5.^[5][15] Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.^[18][19]

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.^[17] 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.^[17]

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.^[20]

Role in iron metabolism

Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell.^[8] 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.^[21]

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.^[22]

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.^[23]

References

1. GRCh38: Ensembl release 89: ENSG00000138449 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025993 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, et al. (February 2000). "Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter". Nature. 403 (6771): 776–781. Bibcode:2000Natur.403..776D. doi:10.1038/35001596. PMID 10693807. S2CID 4429026.
6. Ward DM, Kaplan J (September 2012). "Ferroportin-mediated iron transport: expression and regulation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1426–1433. doi:10.1016/j.bbamcr.2012.03.004. PMC 3718258. PMID 22440327.
7. Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P (January 2006). "Comparative studies of duodenal and macrophage ferroportin proteins". American Journal of Physiology. Gastrointestinal and Liver Physiology. 290 (1): G156–G163. doi:10.1152/ajpgi.00227.2005. PMID 16081760.
8. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. (December 2004). "Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization". Science. 306 (5704): 2090–2093. Bibcode:2004Sci...306.2090N. doi:10.1126/science.1104742. PMID 15514116. S2CID 24035970.
9. "SLC11A3 iron transporter [Homo sapiens]". Protein - NCBI.
10. Zohn IE, De Domenico I, Pollock A, Ward DM, Goodman JF, Liang X, et al. (May 2007). "The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease". Blood. 109 (10): 4174–4180. doi:10.1182/blood-2007-01-066068. PMC 1885502. PMID 17289807.
11. Taniguchi R, Kato HE, Font J, Deshpande CN, Wada M, Ito K, et al. (October 2015). "Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin". Nature Communications. 6 (1): 8545. Bibcode:2015NatCo...6.8545T. doi:10.1038/ncomms9545. PMC 4633820. PMID 26461048.
12. Deshpande CN, Ruwe TA, Shawki A, Xin V, Vieth KR, Valore EV, et al. (August 2018). "Calcium is an essential cofactor for metal efflux by the ferroportin transporter family". Nature Communications. 9 (1): 3075. Bibcode:2018NatCo...9.3075D. doi:10.1038/s41467-018-05446-4. PMC 6079014. PMID 30082682.
13. Mitchell CJ, Shawki A, Ganz T, Nemeth E, Mackenzie B (March 2014). "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. doi:10.1152/ajpcell.00348.2013. PMC 4042619. PMID 24304836.
14. Madejczyk MS, Ballatori N (March 2012). "The iron transporter ferroportin can also function as a manganese exporter". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1818 (3): 651–657. doi:10.1016/j.bbamem.2011.12.002. PMC 5695046. PMID 22178646.
15. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (March 2005). "The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis". Cell Metabolism. 1 (3): 191–200. doi:10.1016/j.cmet.2005.01.003. PMID 16054062.
16. Delaby C, Pilard N, Puy H, Canonne-Hergaux F (April 2008). "Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression" (PDF). The Biochemical Journal. 411 (1): 123–131. doi:10.1042/BJ20071474. PMID 18072938.
17. Mao J, McKean DM, Warrier S, Corbin JG, Niswander L, Zohn IE (September 2010). "The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure". Development. 137 (18): 3079–3088. doi:10.1242/dev.048744. PMC 2926957. PMID 20702562.
18. Felkner MM, Suarez L, Brender J, Scaife B, Hendricks K (December 2005). "Iron status indicators in women with prior neural tube defect-affected pregnancies". Maternal and Child Health Journal. 9 (4): 421–428. doi:10.1007/s10995-005-0017-3. PMID 16315101. S2CID 13415844.
19. Groenen PM, van Rooij IA, Peer PG, Ocké MC, Zielhuis GA, Steegers-Theunissen RP (June 2004). "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. doi:10.1093/jn/134.6.1516. PMID 15173422.
20. 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.
21. Ganz T (April 2011). "Hepcidin and iron regulation, 10 years later". Blood. 117 (17): 4425–4433. doi:10.1182/blood-2011-01-258467. PMC 3099567. PMID 21346250.
22. Sangokoya C, Doss JF, Chi JT (April 2013). "Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin". PLOS Genetics. 9 (4): e1003408. doi:10.1371/journal.pgen.1003408. PMC 3616902. PMID 23593016.
23. "TCDB » SEARCH: 2.A.100.2 members". tcdb.org.

Further reading

• Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, et al. (May 2005). "In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations". Blood. 105 (10): 4096–4102. doi:10.1182/blood-2004-11-4502. PMID 15692071.
• Pietrangelo A (2004). "The ferroportin disease". Blood Cells, Molecules & Diseases. 32 (1): 131–138. doi:10.1016/j.bcmd.2003.08.003. PMID 14757427.
• Robson KJ, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, et al. (October 2004). "Recent advances in understanding haemochromatosis: a transition state". Journal of Medical Genetics. 41 (10): 721–730. doi:10.1136/jmg.2004.020644. PMC 1735598. PMID 15466004.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Abboud S, Haile DJ (June 2000). "A novel mammalian iron-regulated protein involved in intracellular iron metabolism". The Journal of Biological Chemistry. 275 (26): 19906–19912. doi:10.1074/jbc.M000713200. PMID 10747949.
• Haile DJ (2000). "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. doi:10.1159/000015522. PMID 10828623. S2CID 6098716.
• McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, et al. (February 2000). "A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation". Molecular Cell. 5 (2): 299–309. doi:10.1016/S1097-2765(00)80425-6. PMID 10882071.
• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, et al. (July 2001). "A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis". Nature Genetics. 28 (3): 213–214. doi:10.1038/90038. PMID 11431687. S2CID 7345473.
• Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. (August 2001). "Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene". The Journal of Clinical Investigation. 108 (4): 619–623. doi:10.1172/JCI13468. PMC 209405. PMID 11518736.
• Press RD (December 2001). "Hemochromatosis caused by mutations in the iron-regulatory proteins ferroportin and H ferritin". Molecular Diagnosis. 6 (4): 347. doi:10.1054/modi.2001.0060347. PMID 11774199.
• Lee PL, Gelbart T, West C, Halloran C, Felitti V, Beutler E (2001). "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. doi:10.1006/bcmd.2001.0445. PMID 11783942.
• Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA (April 2002). "Intestinal expression of genes involved in iron absorption in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology. 282 (4): G598–G607. doi:10.1152/ajpgi.00371.2001. PMID 11897618.
• Thomas C, Oates PS (April 2002). "IEC-6 cells are an appropriate model of intestinal iron absorption in rats". The Journal of Nutrition. 132 (4): 680–687. doi:10.1093/jn/132.4.680. PMID 11925460.
• Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN (July 2002). "Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis". Blood. 100 (2): 692–694. doi:10.1182/blood.v100.2.692. PMID 12091366.
• Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (July 2002). "Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3)". Blood. 100 (2): 695–697. doi:10.1182/blood-2001-11-0132. PMID 12091367.
• Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, et al. (July 2002). "A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4". Blood. 100 (2): 733–734. doi:10.1182/blood-2002-03-0693. PMID 12123233.

External links

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

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