Ferroportin (SLC40A1/FPN1/IREG1) is the sole known mammalian cellular iron exporter, functioning as a 12-transmembrane domain protein in the Major Facilitator Superfamily (MFS). It exports ferrous iron (Fe2+) from the cytoplasm across the plasma membrane via an electroneutral 2H+/Fe2+ antiport mechanism. Ferroportin is predominantly localized to the basolateral membrane of duodenal enterocytes (for dietary iron absorption), macrophages of the reticuloendothelial system (for iron recycling from senescent erythrocytes), hepatocytes (for iron store mobilization), and erythrocytes. The protein is negatively regulated by the peptide hormone hepcidin (HAMP), which binds to ferroportin in a metal-dependent manner (Fe2+ increases hepcidin affinity ~80-fold), blocking transport and triggering ubiquitination via RNF217 and subsequent lysosomal/proteasomal degradation. Ferroportin works in concert with extracellular ferroxidases (ceruloplasmin, hephaestin) that oxidize exported Fe2+ to Fe3+ for loading onto transferrin. Mutations in SLC40A1 cause hemochromatosis type 4 (ferroportin disease), with loss-of-function mutations causing macrophage iron retention and gain-of-function (hepcidin-resistant) mutations causing parenchymal iron overload.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005381 iron ion transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ferroportin is definitively established as an iron transmembrane transporter. IBA annotation based on phylogenetic inference is well-supported by extensive experimental evidence across vertebrates including human. Reason: This is the core molecular function of ferroportin. The protein exports Fe2+ across the plasma membrane as demonstrated by multiple experimental studies including functional assays in Xenopus oocytes and mammalian cells. Cryo-EM structures have revealed the iron-binding sites and transport mechanism. Supporting Evidence: PMID:15692071 2005 Feb 3. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. PMID:32814342 Aug 19. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. file:human/SLC40A1/SLC40A1-deep-research-falcon.md SLC40A1 encodes ferroportin, the sole known cellular iron exporter in mammals. It exports ferrous iron (Fe2+) across the plasma membrane, cooperating with extracellular ferroxidases (hephaestin, ceruloplasmin) to load iron onto transferrin. |
| GO:0034755 iron ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Iron ion transmembrane transport is the core biological process of ferroportin, well-supported by phylogenetic inference and extensive experimental data. Reason: This biological process annotation directly corresponds to ferroportin's established role as the sole mammalian iron exporter. Supported by IBA phylogenetic analysis and corroborated by multiple experimental studies. Supporting Evidence: PMID:12091367 Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). |
| GO:0016323 basolateral plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Basolateral membrane localization is critical for ferroportin's physiological function in polarized epithelial cells, particularly enterocytes. Reason: Ferroportin localizes to the basolateral membrane of polarized cells including duodenal enterocytes and hepatocytes, enabling iron export into the circulation. This localization is essential for its role in dietary iron absorption and iron homeostasis. Supporting Evidence: PMID:10882071 A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. |
| GO:0017046 peptide hormone binding | IBA GO_REF:0000033 | ACCEPT | Summary: Ferroportin directly binds the peptide hormone hepcidin (HAMP), which is the master regulator of systemic iron homeostasis. Reason: Hepcidin binding to ferroportin is a well-established regulatory mechanism. Structural studies have mapped the hepcidin-binding site within the ferroportin central cavity, with key residues including N144, C326, Y501, and D504. Iron binding increases hepcidin affinity approximately 80-fold. Supporting Evidence: PMID:29237594 2017 Dec 13. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. PMID:32814342 Aug 19. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. |
| GO:0005381 iron ion transmembrane transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on combined automated methods supports the core iron transporter function. Reason: This IEA annotation is consistent with the well-established function of ferroportin and is supported by stronger experimental evidence (IDA, IMP) for the same term. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localization is well-established for ferroportin. Reason: Ferroportin is a multi-pass transmembrane protein (12 TM domains) localized to the plasma membrane where it functions as an iron exporter. This IEA annotation is supported by multiple IDA annotations and structural data. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000043 | ACCEPT | Summary: General ion transport annotation based on UniProt keyword mapping. Reason: While this is a broad annotation, it is accurate - ferroportin transports ferrous iron ions. More specific annotations (iron ion transmembrane transport) are also present. |
| GO:0006826 iron ion transport | IEA GO_REF:0000043 | ACCEPT | Summary: Iron ion transport annotation from UniProt keyword mapping is accurate. Reason: Ferroportin's primary function is iron ion transport. This annotation is correct and supported by extensive experimental evidence for this gene. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Generic membrane annotation from InterPro domain mapping. Reason: Ferroportin is an integral membrane protein with 12 transmembrane helices. While this is a broad annotation, it is accurate. More specific plasma membrane and basolateral membrane annotations are also present. |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for basolateral localization supports the IBA and IDA annotations. Reason: Basolateral membrane localization is well-documented experimentally (IDA from PMID:10882071, PMID:20019163, PMID:29792530). This IEA annotation is consistent. |
| GO:0034755 iron ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain mapping for the Ferroportin-1 domain. Reason: This annotation is consistent with ferroportin's well-established function and is supported by IBA and IMP evidence for the same term. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: Metal ion binding annotation from UniProt keyword mapping. Reason: Ferroportin binds ferrous iron (Fe2+) during transport. Cryo-EM structures have identified two metal-binding sites in the central cavity. This annotation is accurate though general. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000117 | ACCEPT | Summary: Broad transmembrane transport annotation from ARBA machine learning. Reason: Ferroportin is a transmembrane transporter. This is a general but accurate annotation, with more specific annotations (iron ion transmembrane transport) also present. |
| GO:0005515 protein binding | IPI PMID:20817278 Iron-export ferroxidase activity of Ξ²-amyloid precursor prot... | MODIFY | Summary: Interaction with APP (amyloid precursor protein) detected by physical interaction studies. Reason: While the interaction with APP is documented, 'protein binding' is too vague to be informative. The APP interaction relates to iron export regulation in brain cells. A more specific term should be used. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:20817278 Iron-export ferroxidase activity of Ξ²-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. PMID:24867889 sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. |
| GO:0005515 protein binding | IPI PMID:24867889 sAPP modulates iron efflux from brain microvascular endothel... | MODIFY | Summary: Duplicate annotation for APP-ferroportin interaction from different study. Reason: Same as above - protein binding is uninformative. The interaction with soluble APP (sAPP) stabilizes ferroportin at the membrane. Should use more specific term. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:24867889 sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. |
| GO:0008021 synaptic vesicle | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Synaptic vesicle localization transferred from mouse ortholog via Ensembl Compara. Reason: While ferroportin is expressed in neural tissues including astrocytes and microglia, the primary localization is plasma membrane/basolateral membrane. Synaptic vesicle localization is not well-supported as a major site of ferroportin function. This may be an over-annotation based on high-throughput proteomics data. |
| GO:0015093 ferrous iron transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ferrous iron transporter activity transferred from mouse ortholog. Reason: Ferroportin specifically exports ferrous iron (Fe2+). This is more specific than the general iron transporter term and accurately describes the substrate. Supported by IDA evidence from PMID:15692071. |
| GO:0017046 peptide hormone binding | IEA GO_REF:0000107 | ACCEPT | Summary: Hepcidin (peptide hormone) binding transferred from mouse ortholog. Reason: Ferroportin binds hepcidin, the master regulator peptide hormone. This is supported by IDA (PMID:29237594) and IPI (PMID:22682227) evidence. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Homo-oligomerization transferred from mouse ortholog. Reason: There is evidence for ferroportin homo-dimerization. While not extensively characterized, this annotation is reasonable based on ortholog inference. |
| GO:1903988 iron ion export across plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Iron export annotation transferred from mouse ortholog. Reason: This is the most specific and accurate biological process annotation for ferroportin - it exports iron across the plasma membrane. Supported by ISS evidence from GO_REF:0000024. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization from immunofluorescence data curation. Reason: Direct experimental evidence for plasma membrane localization is well-established. |
| GO:1903988 iron ion export across plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Iron export annotation from sequence similarity to mouse ortholog. Reason: This ISS annotation is well-supported by the conserved function of ferroportin across vertebrates. Mouse ferroportin has been extensively characterized and functions identically. |
| GO:0015093 ferrous iron transmembrane transporter activity | IDA PMID:15692071 In vitro functional analysis of human ferroportin (FPN) and ... | ACCEPT | Summary: Direct experimental evidence for ferrous iron transport activity from functional assays. Reason: This IDA annotation provides direct experimental evidence for ferroportin's ferrous iron transport activity. Schimanski et al. demonstrated iron transport using functional assays and characterized disease-associated mutations. Supporting Evidence: PMID:15692071 2005 Feb 3. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. |
| GO:0016323 basolateral plasma membrane | IDA PMID:10882071 A novel duodenal iron-regulated transporter, IREG1, implicat... | ACCEPT | Summary: Original discovery paper establishing basolateral localization in enterocytes. Reason: McKie et al. (2000) identified IREG1/ferroportin and demonstrated its basolateral membrane localization in duodenal enterocytes, establishing its role in iron transfer to the circulation. Supporting Evidence: PMID:10882071 A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. |
| GO:0005515 protein binding | IPI PMID:37277838 Apo- and holo-transferrin differentially interact with hepha... | MODIFY | Summary: Interaction with transferrin (TF) and hephaestin (HEPH) in iron release complex. Reason: Protein binding is uninformative. This study describes a functional complex of ferroportin, hephaestin, and transferrin that regulates cellular iron release. More specific terms should be used. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:37277838 Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation. |
| GO:0017046 peptide hormone binding | IDA PMID:29237594 Structure-function analysis of ferroportin defines the bindi... | ACCEPT | Summary: Direct demonstration of hepcidin binding to ferroportin with structure-function analysis. Reason: Aschemeyer et al. provided detailed structure-function analysis defining the hepcidin binding site on ferroportin and demonstrating that mutations at key residues (N144D, Y501C, D504N) abolish hepcidin binding. Supporting Evidence: PMID:29237594 2017 Dec 13. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. |
| GO:0016323 basolateral plasma membrane | IDA PMID:29792530 Manganese transport and toxicity in polarized WIF-B hepatocy... | ACCEPT | Summary: Basolateral localization in polarized hepatocyte model (WIF-B cells). Reason: Thompson et al. demonstrated ferroportin localization to the basolateral membrane of polarized WIF-B hepatocytes, consistent with its role in hepatic iron export. Supporting Evidence: PMID:29792530 Manganese transport and toxicity in polarized WIF-B hepatocytes. |
| GO:0005886 plasma membrane | IDA PMID:30247984 Ferroportin disease mutations influence manganese accumulati... | ACCEPT | Summary: Plasma membrane localization demonstrated in disease mutation study. Reason: Choi et al. confirmed plasma membrane localization of wild-type ferroportin and showed that certain disease mutations (G80S, D157G, R88G) disrupt cell surface localization. Supporting Evidence: PMID:30247984 Ferroportin disease mutations influence manganese accumulation and cytotoxicity. |
| GO:0005381 iron ion transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Iron transporter activity from sequence similarity to mouse ferroportin. Reason: Human and mouse ferroportin are highly conserved and functionally equivalent. This ISS annotation is well-supported. |
| GO:0015093 ferrous iron transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Ferrous iron transporter activity from mouse ortholog similarity. Reason: Supported by direct experimental evidence (IDA from PMID:15692071) and conserved function in mouse. |
| GO:0016323 basolateral plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Basolateral localization from mouse ortholog similarity. Reason: Well-supported by multiple IDA annotations and consistent with polarized epithelial cell biology. |
| GO:0060586 multicellular organismal-level iron ion homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Systemic iron homeostasis annotation from mouse ortholog. Reason: Ferroportin is the key regulator of systemic iron homeostasis by controlling iron entry into plasma from diet (enterocytes) and stores (macrophages, hepatocytes). Mouse knockout models demonstrate this role, and human mutations cause hemochromatosis type 4. |
| GO:0017046 peptide hormone binding | IPI PMID:22682227 Hepcidin-induced endocytosis of ferroportin is dependent on ... | ACCEPT | Summary: Hepcidin binding demonstrated in ubiquitination study. Reason: Qiao et al. showed that hepcidin binding to ferroportin triggers ubiquitination at lysine residues, leading to endocytosis and degradation. Supporting Evidence: PMID:22682227 Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655733 | ACCEPT | Summary: Plasma membrane annotation from Reactome pathway for defective SLC40A1. Reason: Reactome pathway curation correctly places ferroportin at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655760 | ACCEPT | Summary: Plasma membrane annotation from Reactome pathway. Reason: Consistent with established localization. |
| GO:0005886 plasma membrane | IDA PMID:20019163 Human hephaestin expression is not limited to enterocytes of... | ACCEPT | Summary: Plasma membrane localization from hephaestin co-localization study. Reason: Hudson et al. demonstrated ferroportin plasma membrane localization in various tissues including duodenum and pancreatic beta-cells. Supporting Evidence: PMID:20019163 Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells. |
| GO:0016323 basolateral plasma membrane | IDA PMID:20019163 Human hephaestin expression is not limited to enterocytes of... | ACCEPT | Summary: Basolateral localization from same hephaestin study. Reason: Direct demonstration of basolateral ferroportin localization. Supporting Evidence: PMID:20019163 Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-442368 | ACCEPT | Summary: Reactome annotation for iron transport reaction. Reason: Reactome pathway R-HSA-442368 describes SLC40A1:HEPH:6Cu2+ transporting Fe2+ from cytosol to extracellular region, correctly placing ferroportin at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5621402 | ACCEPT | Summary: Reactome annotation for ceruloplasmin deficiency pathway. Reason: Correct localization in Reactome iron metabolism pathways. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-904830 | ACCEPT | Summary: Reactome annotation for iron transport with ceruloplasmin. Reason: Correct localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917891 | ACCEPT | Summary: Reactome annotation for iron oxidation reaction. Reason: Correct localization in Reactome iron oxidation pathway. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-917933 | ACCEPT | Summary: Reactome annotation for hephaestin-mediated iron oxidation. Reason: Correct localization. |
| GO:0005886 plasma membrane | IC PMID:12091367 Autosomal dominant reticuloendothelial iron overload associa... | ACCEPT | Summary: Plasma membrane localization inferred from iron transporter function. Reason: Curator inference from demonstrated iron transporter activity. Supported by direct experimental evidence. Supporting Evidence: PMID:12091367 Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). |
| GO:0005381 iron ion transmembrane transporter activity | IMP PMID:12091367 Autosomal dominant reticuloendothelial iron overload associa... | ACCEPT | Summary: Iron transporter activity from mutant phenotype analysis. Reason: Devalia et al. demonstrated that the V162del mutation in ferroportin causes iron overload disease, establishing the gene's role in iron transport through genetic evidence. Supporting Evidence: PMID:12091367 Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). |
| GO:0006879 intracellular iron ion homeostasis | IMP PMID:12091367 Autosomal dominant reticuloendothelial iron overload associa... | ACCEPT | Summary: Intracellular iron homeostasis role from genetic evidence. Reason: Mutations in ferroportin disrupt cellular iron homeostasis, causing iron retention in macrophages and other cells. This is a core function. Supporting Evidence: PMID:12091367 Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). |
| GO:0034755 iron ion transmembrane transport | IMP PMID:12091367 Autosomal dominant reticuloendothelial iron overload associa... | ACCEPT | Summary: Iron transmembrane transport from genetic evidence. Reason: The disease phenotype demonstrates ferroportin's essential role in iron transmembrane transport. Supporting Evidence: PMID:12091367 Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). |
| GO:0005886 plasma membrane | IDA GO_REF:0000054 | ACCEPT | Summary: Plasma membrane localization from fusion protein localization studies. Reason: Direct experimental evidence from LIFEdb localization studies. |
| GO:0005737 cytoplasm | TAS PMID:10747949 A novel mammalian iron-regulated protein involved in intrace... | MARK AS OVER ANNOTATED | Summary: Cytoplasm annotation from early discovery paper. Reason: The primary localization of ferroportin is plasma membrane, not cytoplasm. While there may be cytoplasmic pools during trafficking or after hepcidin-induced internalization, 'cytoplasm' is misleading as a static localization. The 2000 paper was an early characterization that may have detected intracellular pools. Supporting Evidence: PMID:10747949 A novel mammalian iron-regulated protein involved in intracellular iron metabolism. |
| GO:0016020 membrane | TAS PMID:10747949 A novel mammalian iron-regulated protein involved in intrace... | ACCEPT | Summary: Generic membrane annotation from early discovery paper. Reason: Ferroportin is an integral membrane protein. This broad annotation is accurate, though more specific annotations (plasma membrane, basolateral membrane) are more informative. Supporting Evidence: PMID:10747949 A novel mammalian iron-regulated protein involved in intracellular iron metabolism. |
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