Ferroportin

Last updated
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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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

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]

Contents

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]

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
SymbolFPN
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]

Related Research Articles

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload or haemochromatosis indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosis, a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">Beta-2 microglobulin</span> Component of MHC class I molecules

β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells. In humans, the β2 microglobulin protein is encoded by the B2M gene.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. It is now recognized to actually be two disorders with different causes, possibly compounding each other:

<span class="mw-page-title-main">HFE (gene)</span>

Human homeostatic iron regulator protein, also known as the HFE protein, is a transmembrane protein that in humans is encoded by the HFE gene. The HFE gene is located on short arm of chromosome 6 at location 6p22.2

<span class="mw-page-title-main">Hemojuvelin</span>

Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene. Hemojuvelin is a member of the repulsive guidance molecule family of proteins. Both RGMa and RGMb are found in the nervous system, while hemojuvelin is found in skeletal muscle and the liver.

Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.

<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

Iron is an important biological element. It is used in both the ubiquitous iron-sulfur proteins and in vertebrates it is used in hemoglobin which is essential for blood and oxygen transport.

<span class="mw-page-title-main">ABCA1</span> Mammalian protein found in Homo sapiens

ATP-binding cassette transporter ABCA1, also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.

<span class="mw-page-title-main">Transferrin receptor 2</span> Mammalian protein found in Homo sapiens

Transferrin receptor 2 (TfR2) is a protein that in humans is encoded by the TFR2 gene. This protein is involved in the uptake of transferrin-bound iron into cells by endocytosis, although its role is minor compared to transferrin receptor 1.

<span class="mw-page-title-main">Iron metabolism disorder</span> Medical condition

Iron metabolism disorders may involve a number of genes including HFE and TFR2.

Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of hereditary hemochromatosis, which emerges in young individuals, typically between 15 and 30 years of age, but occasionally later. It is characterized by an inability to control how much iron is absorbed by the body, in turn leading to iron overload, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates.

<span class="mw-page-title-main">FOXD3</span> Protein-coding gene in the species Homo sapiens

Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.

Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. The first confirmed case was diagnosed in 1865 by French doctor Trousseau. Later in 1889, the German doctor von Recklinghausen indicated that the liver contains iron, and due to bleeding being considered to be the cause, he called the pigment "Haemochromatosis." In 1935, English doctor Sheldon's groundbreaking book titled, Haemochromatosis, reviewed 311 patient case reports and presented the idea that haemochromatosis was a congenital metabolic disorder. Hereditary haemochromatosis is a congenital disorder which affects the regulation of iron metabolism thus causing increased gut absorption of iron and a gradual build-up of pathologic iron deposits in the liver and other internal organs, joint capsules and the skin. The iron overload could potentially cause serious disease from the age of 40–50 years. In the final stages of the disease, the major symptoms include liver cirrhosis, diabetes and bronze-colored skin. There are four types of hereditary hemochromatosis which are classified depending on the age of onset and other factors such as genetic cause and mode of inheritance.

<span class="mw-page-title-main">Erythroferrone</span>

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

<span class="mw-page-title-main">Zinc transporter ZIP12</span> Protein found in humans

Solute carrier family 39 member 12 is a protein that in humans is encoded by the SLC39A12 gene.

A heme transporter is a protein that delivers heme to the various parts of a biological cell that require it.

References

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Further reading

As of this edit, this article uses content from "2.A.100 The Ferroportin (Fpn) Family" , which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed.