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, and is part of the Ferroportin (Fpn) Family (TC# 2.A.100). 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 and function
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.
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, ferroportin has been shown to transport cobalt & zinc, as well as nickel. Ferroportin may also function as a manganese exporter.
Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including:
- Enterocytes in the duodenum
- Macrophages of the reticuloendothelial system
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.
Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as type IV haemochromatosis 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.
- ↑ 1.0 1.1 "Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter". Nature 403 (6771): 776–781. February 2000. doi:10.1038/35001596. PMID 10693807. Bibcode: 2000Natur.403..776D.
- ↑ "Ferroportin-mediated iron transport: expression and regulation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1823 (9): 1426–1433. September 2012. doi:10.1016/j.bbamcr.2012.03.004. PMID 22440327.
- ↑ "Comparative studies of duodenal and macrophage ferroportin proteins". American Journal of Physiology. Gastrointestinal and Liver Physiology 290 (1): G156–G163. January 2006. doi:10.1152/ajpgi.00227.2005. PMID 16081760.
- ↑ 4.0 4.1 "Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization". Science 306 (5704): 2090–2093. December 2004. doi:10.1126/science.1104742. PMID 15514116. Bibcode: 2004Sci...306.2090N.
- ↑ 5.0 5.1 "SLC11A3 iron transporter [Homo sapiens"]. Protein - NCBI. https://www.ncbi.nlm.nih.gov/protein/AAF80986.1?report=gpwithparts&log$=seqview.
- ↑ "The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease". Blood 109 (10): 4174–4180. May 2007. doi:10.1182/blood-2007-01-066068. PMID 17289807.
- ↑ "Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin". Nature Communications 6 (1): 8545. October 2015. doi:10.1038/ncomms9545. PMID 26461048. Bibcode: 2015NatCo...6.8545T.
- ↑ 8.0 8.1 8.2 8.3 "Calcium is an essential cofactor for metal efflux by the ferroportin transporter family". Nature Communications 9 (1): 3075. August 2018. doi:10.1038/s41467-018-05446-4. PMID 30082682. Bibcode: 2018NatCo...9.3075D.
- ↑ "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. doi:10.1152/ajpcell.00348.2013. PMID 24304836.
- ↑ "The iron transporter ferroportin can also function as a manganese exporter". Biochimica et Biophysica Acta (BBA) - Biomembranes 1818 (3): 651–657. March 2012. doi:10.1016/j.bbamem.2011.12.002. PMID 22178646.
- ↑ 11.0 11.1 11.2 "The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis". Cell Metabolism 1 (3): 191–200. March 2005. doi:10.1016/j.cmet.2005.01.003. PMID 16054062.
- ↑ "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. doi:10.1042/BJ20071474. PMID 18072938. https://hal.archives-ouvertes.fr/hal-00478904/file/PEER_stage2_10.1042%252FBJ20071474.pdf.
- ↑ 13.0 13.1 13.2 "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. doi:10.1242/dev.048744. PMID 20702562.
- ↑ "Iron status indicators in women with prior neural tube defect-affected pregnancies". Maternal and Child Health Journal 9 (4): 421–428. December 2005. doi:10.1007/s10995-005-0017-3. PMID 16315101.
- ↑ "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. doi:10.1093/jn/134.6.1516. PMID 15173422.
- ↑ 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.
- ↑ "Hepcidin and iron regulation, 10 years later". Blood 117 (17): 4425–4433. April 2011. doi:10.1182/blood-2011-01-258467. PMID 21346250.
- ↑ "Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin". PLOS Genetics 9 (4): e1003408. April 2013. doi:10.1371/journal.pgen.1003408. PMID 23593016.
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- ferroportin1+protein at the US National Library of Medicine Medical Subject Headings (MeSH)
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