Existing Annotations Review

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 β-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 β-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.

Core Functions

Ferroportin is the sole known mammalian iron exporter. It specifically transports ferrous iron (Fe2+) from the cytoplasm to the extracellular space via an electroneutral 2H+/Fe2+ antiport mechanism. This function has been demonstrated by direct transport assays in Xenopus oocytes and mammalian cells (PMID:15692071, PMID:24304836), cryo-EM structural analysis revealing iron-binding sites (PMID:32814342), and genetic evidence from hemochromatosis type 4 patients (PMID:12091367).

Molecular Function:

ferrous iron transmembrane transporter activity

Ferroportin directly binds the peptide hormone hepcidin (HAMP), which is the master regulator of systemic iron homeostasis. Hepcidin binding blocks iron transport and triggers ferroportin ubiquitination and degradation. Structural studies have mapped the hepcidin-binding site (PMID:29237594, PMID:32814342). Iron binding to ferroportin increases hepcidin affinity ~80-fold, ensuring hepcidin preferentially targets iron-loaded ferroportin.

Molecular Function:

peptide hormone binding

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000054

Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10747949

A novel mammalian iron-regulated protein involved in intracellular iron metabolism.

Original discovery of MTP1/ferroportin identifying it as an iron-regulated protein involved in iron metabolism.

"We have isolated and characterized a novel iron-regulated gene that is homologous to the divalent metal transporter 1 family of metal transporters"

PMID:10882071

A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.

Identified IREG1 (ferroportin) at the basolateral membrane of duodenal enterocytes

"We describe here the isolation and characterization of a novel cDNA (Ireg1) encoding a duodenal protein that is localized to the basolateral membrane of polarized epithelial cells"
Implicated in transfer of dietary iron to the circulation

"We conclude that IREG1 represents the long-sought duodenal iron export protein"

PMID:12091367

Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).

V162del mutation causes hemochromatosis type 4

"A 3-base pair deletion in exon 5 of the ferroportin 1 gene (SLC11A3) predicting Val162 deletion was found in affected members"
Established genetic evidence for ferroportin role in iron export

"These results indicate that this extracellular cluster is functionally important for iron transport, and its disruption leads to iron overload"

PMID:15692071

In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.

Demonstrated ferrous iron (Fe2+) transport activity

"expression of human FPN in a human cell line results in an iron deficiency because of a 3-fold increased export of iron"
Characterized disease mutations A77D and G490D showing loss of function

"FPN mutations A77D, V162delta, and G490D that are associated with a typical pattern of disease in vivo cause a loss of iron export function in vitro"

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.

Co-localization of ferroportin with hephaestin

"In addition to its expression in the same cells as Hp, ferroportin was also localized to the ductal cells of the exocrine pancreas"
Basolateral membrane localization in multiple tissues

"previous immunocytochemical studies in rat, mouse, and human gut tissues localized Hp to the basolateral membranes of the duodenal enterocytes"

PMID:20817278

Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.

APP interacts with ferroportin to facilitate iron export

"Like ceruloplasmin, APP catalytically oxidizes Fe(2+), loads Fe(3+) into transferrin, and has a major interaction with ferroportin"

PMID:22682227

Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination.

Hepcidin binding triggers ferroportin ubiquitination

"Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages"
Ubiquitination required for endocytosis and degradation

"Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis"

PMID:24867889

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.

Soluble APP stabilizes ferroportin at the membrane

"the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane"
Mechanism of iron export regulation in brain

"in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium"

PMID:29237594

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin.

Mapped hepcidin binding site on ferroportin

"hepcidin binding occurred within the central cavity of Fpn"
Identified key residues N144, Y501, D504 required for binding

"All clinical mutants were functionally resistant to hepcidin as a consequence of either impaired hepcidin binding or impaired hepcidin-dependent ubiquitination despite intact hepcidin binding"
N144D shows complete loss of hepcidin binding

"mutations that caused ubiquitination-resistance were positioned at helix-helix interfaces, likely preventing the hepcidin-induced conformational change"

PMID:29792530

Manganese transport and toxicity in polarized WIF-B hepatocytes.

Ferroportin localized to basolateral membrane in hepatocytes

"Fpn and ZIP14 localize to basolateral domains"
Evidence that Mn2+ is not a physiological substrate

"Hepcidin reduced levels of Fpn in WIF-B cells, clearing Fpn from the cell surface, but Mn efflux was unaffected"

PMID:30247984

Ferroportin disease mutations influence manganese accumulation and cytotoxicity.

Characterized disease mutations affecting localization and function

"disease mutations interfere with the role of Fpn in controlling Mn levels as well as the stability of Fpn"
G80S, D157G lose cell surface localization

"Hemochromatosis is a frequent genetic disorder, characterized by the accumulation of excess iron across tissues"
N144H/T show hepcidin resistance

"These results define the function of Fpn as an exporter of both iron and Mn"

PMID:32814342

Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.

Cryo-EM structure of ferroportin with and without hepcidin

"determine cryogenic electron microscopy structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with hepcidin and the iron mimetic cobalt"
Revealed iron-binding sites and hepcidin binding as molecular cork

"Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway"
12-TM topology confirmed

"hepcidin directly contacts the divalent metal in the ferroportin C domain"

PMID:37277838

Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation.

Ferroportin, hephaestin, and transferrin form functional complex

"holo-Tf directly interacts with ferroportin, whereas apo-Tf directly interacts with hephaestin"
Holo-transferrin promotes ferroportin degradation

"We demonstrate that holo-Tf induces the internalization of ferroportin through the established ferroportin degradation pathway"

Reactome:R-HSA-442368

SLC40A1:HEPH:6Cu2+ transports Fe2+ from cytosol to extracellular region

Reactome:R-HSA-5621402

Defective CP does not oxidise Fe2+ to Fe3+

Reactome:R-HSA-5655733

Defective SLC40A1 does not transport Fe2+ from cytosol to extracellular region

Reactome:R-HSA-5655760

Defective SLC40A1 does not transport Fe3+ from extracellular region to cytosol

Reactome:R-HSA-904830

SLC40A1:CP:6Cu2+ transports Fe2+ from cytosol to extracellular region

Reactome:R-HSA-917891

SLC40A1:CP:6Cu2+ oxidises Fe2+ to Fe3+

Reactome:R-HSA-917933

SLC40A1:HEPH:6Cu2+ oxidises 4Fe2+ to 4Fe3+

📚 Additional Documentation

Deep Research Falcon

(SLC40A1-deep-research-falcon.md)

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template_variables:
organism: human
gene_id: SLC40A1
gene_symbol: SLC40A1
uniprot_accession: Q9NP59
protein_description: 'RecName: Full=Ferroportin {ECO:0000305|PubMed:15692071}; AltName:
Full=Ferroportin-1; AltName: Full=Iron-regulated transporter 1; AltName: Full=Solute
carrier family 40 member 1 {ECO:0000312|HGNC:HGNC:10909};'
gene_info: Name=SLC40A1 {ECO:0000312|HGNC:HGNC:10909}; Synonyms=FPN {ECO:0000303|PubMed:15692071},
FPN1, IREG1, SLC11A3; ORFNames=MSTP079;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A
protein_domains: Ferroportin-1. (IPR009716); MFS_trans_sf. (IPR036259); FPN1 (PF06963)
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citation_count: 16

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9NP59
Protein Description: RecName: Full=Ferroportin {ECO:0000305|PubMed:15692071}; AltName: Full=Ferroportin-1; AltName: Full=Iron-regulated transporter 1; AltName: Full=Solute carrier family 40 member 1 {ECO:0000312|HGNC:HGNC:10909};
Gene Information: Name=SLC40A1 {ECO:0000312|HGNC:HGNC:10909}; Synonyms=FPN {ECO:0000303|PubMed:15692071}, FPN1, IREG1, SLC11A3; ORFNames=MSTP079;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A
Key Domains: Ferroportin-1. (IPR009716); MFS_trans_sf. (IPR036259); FPN1 (PF06963)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SLC40A1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SLC40A1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SLC40A1 (gene ID: SLC40A1, UniProt: Q9NP59) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9NP59
Protein Description: RecName: Full=Ferroportin {ECO:0000305|PubMed:15692071}; AltName: Full=Ferroportin-1; AltName: Full=Iron-regulated transporter 1; AltName: Full=Solute carrier family 40 member 1 {ECO:0000312|HGNC:HGNC:10909};
Gene Information: Name=SLC40A1 {ECO:0000312|HGNC:HGNC:10909}; Synonyms=FPN {ECO:0000303|PubMed:15692071}, FPN1, IREG1, SLC11A3; ORFNames=MSTP079;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A
Key Domains: Ferroportin-1. (IPR009716); MFS_trans_sf. (IPR036259); FPN1 (PF06963)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SLC40A1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SLC40A1 (gene ID: SLC40A1, UniProt: Q9NP59) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity check: The target is human SLC40A1 (UniProt Q9NP59), also known as ferroportin, FPN1, IREG1; member of the solute carrier family 40 (SLC40A). Literature reviewed below consistently refers to human ferroportin/SLC40A1 and the ferroportin (FP) family, with a 12-transmembrane Major Facilitator Superfamily (MFS) fold and hallmark regulation by hepcidin. No conflicting gene symbol usage was encountered. The organism context is Homo sapiens. Family/domain assignments and functional attributes align with the ferroportin (TC 2.A.100) group and MFS-related structural superfamily. (amadei2024investigatingtheferroportinferroxidase pages 20-25, amadei2024investigatingtheferroportinferroxidase pages 25-30)

Comprehensive research report
1) Key concepts and definitions (current understanding)
- Primary function and substrate: 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. (amadei2024investigatingtheferroportinferroxidase pages 20-25, amadei2024investigatingtheferroportinferroxidasea pages 20-25)
- Cellular and tissue localization: Ferroportin is localized to the basolateral membrane of duodenal enterocytes (dietary iron export), is highly expressed in macrophages of the reticuloendothelial system (iron recycling), and hepatocytes (iron release from stores). Additional expression occurs in placenta and cells of the central nervous system (astrocytes/microglia). (amadei2024investigatingtheferroportinferroxidase pages 25-30)
- Structural class/domains: Human FPN is an ~571 aa, 12‑TM transporter with intracellular N- and C-termini, adopting an MFS fold comprising N- (TM1–6) and C- (TM7–12) domains forming a central cavity. TM7 is split into TM7a/TM7b and harbors key residues implicated in metal binding and hepcidin regulation (e.g., D325, C326). (amadei2024investigatingtheferroportinferroxidase pages 25-30)
- Transport stoichiometry: Experimental structural/functional studies support that FPN exports Fe2+ in exchange for protons; mammalian/primate cryo‑EM studies showed electroneutral H+/Fe2+ antiport with two H+ per Fe2+. (eLife/related structural work as collated in 2025 review) (amadei2025thedifferentaffinity pages 11-12)

2) Structural mechanism and hepcidin binding/inhibition (with structural data)
- Conformational cycle: Mammalian FPN structures are captured mainly in outward‑open or partially occluded states; inward‑open states are inferred from bacterial homologs. An intracellular “gating network” (e.g., R88, D157, E486, R489) stabilizes outward‑open conformations; mutations in this network can cause loss‑of‑function disease. (amadei2024investigatingtheferroportinferroxidasea pages 25-30, amadei2024investigatingtheferroportinferroxidase pages 25-30)
- Hepcidin binding site and metal dependence: Cryo‑EM of FPN–metal–hepcidin complexes shows hepcidin binds within the central cavity bridging N‑ and C‑domains, acting as a “molecular cork” that locks an outward‑open state. Key residues at or near the site include N144, D325, C326, Y333, Y501, D504, H507; the hepcidin C‑terminus coordinates a divalent metal at the S2 site. Binding is metal‑dependent; Fe2+ markedly increases hepcidin affinity (~80‑fold), consistent with hepcidin preferentially inhibiting iron‑loaded FPN. (amadei2024investigatingtheferroportinferroxidase pages 35-40, amadei2024investigatingtheferroportinferroxidasea pages 35-40)
- Inhibitor‑bound structures: Recent structural work has reported FPN in complex with the specific small‑molecule inhibitor vamifeport (VIT‑2763), capturing a partially closed/occluded central cavity that rationalizes inhibition. (Lehmann et al., 2023, eLife, DOI: 10.7554/eLife.83053) (amadei2025thedifferentaffinity pages 11-12)
- Evidence for antiport stoichiometry in structure-guided studies: Cryo‑EM analyses of primate FPN (e.g., Philippine tarsier) indicated electroneutral 2H+/1Fe2+ antiport with two metal‑binding sites (one per domain); mutating either site impairs coupled transport. (Pan et al., Biophysical Journal 2021, DOI: 10.1016/j.bpj.2020.11.656) (amadei2024investigatingtheferroportinferroxidase pages 20-25)

3) Regulation: systemic and cellular pathways
- Hepcidin–FPN axis: Hepcidin (25 aa peptide hormone from hepatocytes) is the master systemic regulator. Hepcidin binding to surface FPN blocks transport and triggers FPN ubiquitination, internalization, and degradation. Mechanistic studies indicate recruitment of kinases (e.g., Jak2) and ubiquitin ligases (e.g., RNF217) in internalization/degradation pathways. (domenico12011hepcidinandferroportin pages 8-9, amadei2024investigatingtheferroportinferroxidase pages 35-40)
- Upstream hepcidin regulation: Hepcidin is upregulated by iron and inflammation (e.g., IL‑6/STAT3; BMP/SMAD via BMP6/HJV), and suppressed by erythropoietic drive (e.g., erythroferrone) and hypoxia. These changes modulate FPN activity system‑wide by altering hepcidin levels. (domenico12011hepcidinandferroportin pages 11-13)
- Transcriptional/post‑transcriptional control of SLC40A1: FPN transcription responds to NRF2/ARE and HIF signals (notably HIF‑2α in enterocytes), linking oxidative stress and hypoxia to iron export capacity; post‑transcriptionally, most SLC40A1 transcripts contain a 5′ iron‑responsive element (IRE) that suppresses translation via IRP binding under low cytosolic iron. miRNAs (e.g., miR‑20 family) also modulate FPN expression via the 3′ UTR. (amadei2024investigatingtheferroportinferroxidasea pages 20-25, amadei2024investigatingtheferroportinferroxidasea pages 35-40, amadei2024investigatingtheferroportinferroxidasea pages 152-156)
- Ferroxidases modulate FPN stability: Cell‑surface hephaestin/ceruloplasmin promote iron oxidation/loading and stabilize FPN at the membrane; loss of ferroxidase activity can accelerate hepcidin sensitivity/internalization of FPN. (amadei2024investigatingtheferroportinferroxidase pages 35-40)

4) Disease associations, mutations, and pathophysiology
- Hemochromatosis type 4 (ferroportin disease): Autosomal dominant SLC40A1 mutations cause two clinical patterns: (a) loss‑of‑function (classically “type 4A”) with iron retention in macrophages, high ferritin but normal/low transferrin saturation; (b) hepcidin‑resistant gain‑of‑function (“type 4B”) with high transferrin saturation and parenchymal iron overload similar to classic hemochromatosis. (domenico12011hepcidinandferroportin pages 11-13)
- Mechanistic mutation classes: Mutations that disrupt transport/localization or the intracellular gate produce loss‑of‑function; mutations near the hepcidin‑binding/metal site (e.g., C326, Y333, D325) can confer hepcidin resistance. Structural reviews highlight residues D157 (gate), D325/C326 (TM7b metal/hepcidin interface), and Y333 (hepcidin pocket) as critical. (amadei2024investigatingtheferroportinferroxidasea pages 25-30, amadei2024investigatingtheferroportinferroxidase pages 35-40)
- Anemia of inflammation: Elevated hepcidin during inflammation blocks FPN‑mediated iron export from enterocytes and macrophages, restricting plasma iron and contributing to iron‑restricted erythropoiesis. (domenico12011hepcidinandferroportin pages 11-13)

5) Recent developments and latest research (2023–2024 focus)
- Structural advances: 2023 cryo‑EM studies reported FPN in complex with the small‑molecule inhibitor vamifeport, providing atomistic insight into pharmacologic inhibition and an occluded/closed central cavity. These data complement earlier hepcidin‑bound structures and support an elevator‑like or rocker‑switch cycle biased by intracellular and extracellular gating networks. eLife 2023 (DOI: 10.7554/eLife.83053). (amadei2025thedifferentaffinity pages 11-12)
- Mechanism updates: Contemporary analyses emphasize a split TM7 with dynamic TM7b stabilized by bound metal, formation of two metal sites (one per domain), and a metal‑dependent increase in hepcidin affinity that may tune inhibition to iron‑loaded FPN. (amadei2024investigatingtheferroportinferroxidasea pages 25-30, amadei2024investigatingtheferroportinferroxidase pages 35-40)

6) Current applications and translational implementations
- Hepcidin agonists (mimetics): Rusfertide (PTG‑300) is a clinical hepcidin mimetic advancing in late‑stage development for polycythemia vera; clinical studies show reduction/elimination of therapeutic phlebotomy requirements and normalization of hematologic/iron parameters. (Review coverage of ongoing late‑stage trials and results) (domenico12011hepcidinandferroportin pages 11-13)
- Ferroportin inhibitor: Vamifeport (VIT‑2763) is an oral small‑molecule FPN blocker in clinical development; it has been reported as the only FPN blocker in human testing to date in several recent reviews and summaries. (amadei2024investigatingtheferroportinferroxidase pages 25-30)
- Broader therapeutic landscape: Multiple agents target the hepcidin/FPN axis directly or indirectly (e.g., ALK2/BMP pathway inhibitors or TMPRSS6 modulation), with intent to correct iron maldistribution in disorders with ineffective erythropoiesis or inflammatory anemia. (guerra2023novelpotentialtherapeutics pages 5-5)

7) Quantitative data and statistics
- Transport stoichiometry: Structural/functional evidence indicates electroneutral antiport with two protons per exported Fe2+ (2H+/Fe2+). (Pan et al., Biophysical Journal 2021, DOI: 10.1016/j.bpj.2020.11.656) (amadei2024investigatingtheferroportinferroxidase pages 20-25)
- Metal‑dependent hepcidin affinity: Binding of Fe2+ markedly increases hepcidin affinity to FPN (approximately 80‑fold), consistent with a model in which hepcidin preferentially targets iron‑occupied FPN. (amadei2024investigatingtheferroportinferroxidasea pages 35-40)
- Clinical development notes: Reviews summarizing recent trial activity indicate rusfertide has shown robust hematocrit control and phlebotomy elimination in phase 2 PV studies and is in a global phase 3 trial; vamifeport has completed early‑phase clinical testing as an oral FPN inhibitor. (amadei2024investigatingtheferroportinferroxidase pages 25-30, guerra2023novelpotentialtherapeutics pages 5-5)

Expert analysis and synthesis
- SLC40A1/ferroportin represents the systemic bottleneck for iron entry into plasma from diet and stores. The convergence of structure, biophysics, and pathophysiology now supports a cohesive model wherein FPN exports Fe2+ via 2H+ antiport, is directly corked by hepcidin in a metal‑dependent manner, and is subsequently removed by ubiquitin‑mediated endocytosis. Structural localization of disease mutations to the intracellular gate or the hepcidin/metal site explains the dichotomy of ferroportin disease phenotypes (loss of transport vs hepcidin resistance). Therapeutic manipulation of this axis—either amplifying hepcidin activity (agonists) or directly inhibiting FPN (vamifeport)—is yielding clinically meaningful effects in iron‑loading and erythrocytosis disorders, with continued momentum in 2023–2024.

Citations (with URLs and dates where available)
- Amadei M. Investigating the ferroportin–ferroxidase system. 2024. Summary of identity, localization, structural features (MFS fold), gating, and hepcidin–metal mechanistic insights. (amadei2024investigatingtheferroportinferroxidasea pages 25-30, amadei2024investigatingtheferroportinferroxidase pages 35-40, amadei2024investigatingtheferroportinferroxidase pages 20-25, amadei2024investigatingtheferroportinferroxidase pages 25-30, amadei2024investigatingtheferroportinferroxidasea pages 20-25, amadei2024investigatingtheferroportinferroxidasea pages 35-40)
- Amadei M, De Lauro A, Polticelli F, Musci G, Bonaccorsi di Patti M.C. The different affinity of the two metal-binding sites of human ferroportin drives outward directionality of transport. Biometals. Jul 2025. Includes references to 2023 cryo‑EM structures with vamifeport and hepcidin, and mechanistic updates. URL: https://doi.org/10.1007/s10534-025-00725-2 (amadei2025thedifferentaffinity pages 11-12)
- Pan Y. et al. Structural Basis of Ion Transport and Inhibition in Ferroportin. Biophysical Journal 120(3):72a. Feb 2021. Cryo‑EM of primate FPN; 2H+/Fe2+ antiport; hepcidin binding between domains. DOI: 10.1016/j.bpj.2020.11.656 (amadei2024investigatingtheferroportinferroxidase pages 20-25)
- De Domenico I, Ward D, Kaplan J. Hepcidin and Iron in Health and Disease (Seminars in Liver Disease). Aug 2011. Foundational review of hepcidin–ferroportin regulation, internalization mechanisms, and ferroportin disease phenotypes. URL: https://doi.org/10.1055/s-0031-1286058 (domenico12011hepcidinandferroportin pages 8-9, domenico12011hepcidinandferroportin pages 11-13)
- Pascale M.R.D. et al. Iron and Heart Failure: Current Concepts and Emerging Pharmacological Paradigms. World Journal of Cardiovascular Diseases. Jan 2024. Notes that rusfertide is being tested and that vamifeport (VIT‑2763) is an FPN blocker under clinical investigation. URL: https://doi.org/10.4236/wjcd.2024.144016 (amadei2024investigatingtheferroportinferroxidase pages 25-30)
- Guerra A, Parhiz H, Rivella S. Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis. Haematologica. Jun 2023. Summarizes hepcidin/FPN‑targeted agents (rusfertide, vamifeport) and upstream modulators (BMP/SMAD, ERFE). URL: https://doi.org/10.3324/haematol.2023.283057 (guerra2023novelpotentialtherapeutics pages 5-5)

References

(amadei2024investigatingtheferroportinferroxidase pages 20-25): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(amadei2024investigatingtheferroportinferroxidase pages 25-30): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(amadei2024investigatingtheferroportinferroxidasea pages 20-25): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(amadei2025thedifferentaffinity pages 11-12): Matteo Amadei, Alfredo De Lauro, Fabio Polticelli, Giovanni Musci, and Maria Carmela Bonaccorsi di Patti. The different affinity of the two metal-binding sites of human ferroportin drives outward directionality of transport. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine, Jul 2025. URL: https://doi.org/10.1007/s10534-025-00725-2, doi:10.1007/s10534-025-00725-2. This article has 0 citations.
(amadei2024investigatingtheferroportinferroxidasea pages 25-30): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(amadei2024investigatingtheferroportinferroxidase pages 35-40): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(amadei2024investigatingtheferroportinferroxidasea pages 35-40): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(domenico12011hepcidinandferroportin pages 8-9): Ivana De Domenico1, Diane Ward2, and Jerry Kaplan2. Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis, 31:272-279, Aug 2011. URL: https://doi.org/10.1055/s-0031-1286058, doi:10.1055/s-0031-1286058. This article has 149 citations.
(domenico12011hepcidinandferroportin pages 11-13): Ivana De Domenico1, Diane Ward2, and Jerry Kaplan2. Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis, 31:272-279, Aug 2011. URL: https://doi.org/10.1055/s-0031-1286058, doi:10.1055/s-0031-1286058. This article has 149 citations.
(amadei2024investigatingtheferroportinferroxidasea pages 152-156): M Amadei. Investigating the ferroportin-ferroxidase system. Unknown journal, 2024.
(guerra2023novelpotentialtherapeutics pages 5-5): Amaliris Guerra, Hamideh Parhiz, and Stefano Rivella. Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis. Haematologica, 108:2582-2593, Jun 2023. URL: https://doi.org/10.3324/haematol.2023.283057, doi:10.3324/haematol.2023.283057. This article has 19 citations.

Citations

amadei2024investigatingtheferroportinferroxidase pages 25-30
amadei2025thedifferentaffinity pages 11-12
amadei2024investigatingtheferroportinferroxidase pages 20-25
amadei2024investigatingtheferroportinferroxidase pages 35-40
guerra2023novelpotentialtherapeutics pages 5-5
amadei2024investigatingtheferroportinferroxidasea pages 35-40
amadei2024investigatingtheferroportinferroxidasea pages 20-25
amadei2024investigatingtheferroportinferroxidasea pages 25-30
amadei2024investigatingtheferroportinferroxidasea pages 152-156
https://doi.org/10.1007/s10534-025-00725-2
https://doi.org/10.1055/s-0031-1286058
https://doi.org/10.4236/wjcd.2024.144016
https://doi.org/10.3324/haematol.2023.283057
https://doi.org/10.1007/s10534-025-00725-2,
https://doi.org/10.1055/s-0031-1286058,
https://doi.org/10.3324/haematol.2023.283057,

📄 View Raw YAML

id: Q9NP59
gene_symbol: SLC40A1
aliases:
  - FPN
  - FPN1
  - IREG1
  - MTP1
  - SLC11A3
  - ferroportin
  - ferroportin-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0005381
      label: iron ion transmembrane transporter activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:15692071
          supporting_text: 2005 Feb 3. In vitro functional analysis of human 
            ferroportin (FPN) and hemochromatosis-associated FPN mutations.
        - reference_id: PMID:32814342
          supporting_text: Aug 19. Structure of hepcidin-bound ferroportin 
            reveals iron homeostatic mechanisms.
        - reference_id: file:human/SLC40A1/SLC40A1-deep-research-falcon.md
          supporting_text: 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.
  - term:
      id: GO:0034755
      label: iron ion transmembrane transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Iron ion transmembrane transport is the core biological process 
        of ferroportin, well-supported by phylogenetic inference and extensive 
        experimental data.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12091367
          supporting_text: Autosomal dominant reticuloendothelial iron overload 
            associated with a 3-base pair deletion in the ferroportin 1 gene 
            (SLC11A3).
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Basolateral membrane localization is critical for ferroportin's 
        physiological function in polarized epithelial cells, particularly 
        enterocytes.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10882071
          supporting_text: A novel duodenal iron-regulated transporter, IREG1, 
            implicated in the basolateral transfer of iron to the circulation.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Ferroportin directly binds the peptide hormone hepcidin (HAMP), 
        which is the master regulator of systemic iron homeostasis.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:29237594
          supporting_text: 2017 Dec 13. Structure-function analysis of 
            ferroportin defines the binding site and an alternative mechanism of
            action of hepcidin.
        - reference_id: PMID:32814342
          supporting_text: Aug 19. Structure of hepcidin-bound ferroportin 
            reveals iron homeostatic mechanisms.
  - term:
      id: GO:0005381
      label: iron ion transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation based on combined automated methods supports the 
        core iron transporter function.
      action: ACCEPT
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Plasma membrane localization is well-established for ferroportin.
      action: ACCEPT
      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.
  - term:
      id: GO:0006811
      label: monoatomic ion transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: General ion transport annotation based on UniProt keyword 
        mapping.
      action: ACCEPT
      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.
  - term:
      id: GO:0006826
      label: iron ion transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Iron ion transport annotation from UniProt keyword mapping is 
        accurate.
      action: ACCEPT
      reason: Ferroportin's primary function is iron ion transport. This 
        annotation is correct and supported by extensive experimental evidence 
        for this gene.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Generic membrane annotation from InterPro domain mapping.
      action: ACCEPT
      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.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation for basolateral localization supports the IBA and 
        IDA annotations.
      action: ACCEPT
      reason: Basolateral membrane localization is well-documented 
        experimentally (IDA from PMID:10882071, PMID:20019163, PMID:29792530). 
        This IEA annotation is consistent.
  - term:
      id: GO:0034755
      label: iron ion transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro domain mapping for the Ferroportin-1
        domain.
      action: ACCEPT
      reason: This annotation is consistent with ferroportin's well-established 
        function and is supported by IBA and IMP evidence for the same term.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Metal ion binding annotation from UniProt keyword mapping.
      action: ACCEPT
      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.
  - term:
      id: GO:0055085
      label: transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Broad transmembrane transport annotation from ARBA machine 
        learning.
      action: ACCEPT
      reason: Ferroportin is a transmembrane transporter. This is a general but 
        accurate annotation, with more specific annotations (iron ion 
        transmembrane transport) also present.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20817278
    review:
      summary: Interaction with APP (amyloid precursor protein) detected by 
        physical interaction studies.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      additional_reference_ids:
        - PMID:24867889
      supported_by:
        - reference_id: PMID:20817278
          supporting_text: Iron-export ferroxidase activity of β-amyloid 
            precursor protein is inhibited by zinc in Alzheimer's disease.
        - reference_id: PMID:24867889
          supporting_text: sAPP modulates iron efflux from brain microvascular 
            endothelial cells by stabilizing the ferrous iron exporter 
            ferroportin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24867889
    review:
      summary: Duplicate annotation for APP-ferroportin interaction from 
        different study.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:24867889
          supporting_text: sAPP modulates iron efflux from brain microvascular 
            endothelial cells by stabilizing the ferrous iron exporter 
            ferroportin.
  - term:
      id: GO:0008021
      label: synaptic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Synaptic vesicle localization transferred from mouse ortholog via
        Ensembl Compara.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0015093
      label: ferrous iron transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Ferrous iron transporter activity transferred from mouse 
        ortholog.
      action: ACCEPT
      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.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Hepcidin (peptide hormone) binding transferred from mouse 
        ortholog.
      action: ACCEPT
      reason: Ferroportin binds hepcidin, the master regulator peptide hormone. 
        This is supported by IDA (PMID:29237594) and IPI (PMID:22682227) 
        evidence.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Homo-oligomerization transferred from mouse ortholog.
      action: ACCEPT
      reason: There is evidence for ferroportin homo-dimerization. While not 
        extensively characterized, this annotation is reasonable based on 
        ortholog inference.
  - term:
      id: GO:1903988
      label: iron ion export across plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Iron export annotation transferred from mouse ortholog.
      action: ACCEPT
      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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Plasma membrane localization from immunofluorescence data 
        curation.
      action: ACCEPT
      reason: Direct experimental evidence for plasma membrane localization is 
        well-established.
  - term:
      id: GO:1903988
      label: iron ion export across plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Iron export annotation from sequence similarity to mouse 
        ortholog.
      action: ACCEPT
      reason: This ISS annotation is well-supported by the conserved function of
        ferroportin across vertebrates. Mouse ferroportin has been extensively 
        characterized and functions identically.
  - term:
      id: GO:0015093
      label: ferrous iron transmembrane transporter activity
    evidence_type: IDA
    original_reference_id: PMID:15692071
    review:
      summary: Direct experimental evidence for ferrous iron transport activity 
        from functional assays.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:15692071
          supporting_text: 2005 Feb 3. In vitro functional analysis of human 
            ferroportin (FPN) and hemochromatosis-associated FPN mutations.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:10882071
    review:
      summary: Original discovery paper establishing basolateral localization in
        enterocytes.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10882071
          supporting_text: A novel duodenal iron-regulated transporter, IREG1, 
            implicated in the basolateral transfer of iron to the circulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37277838
    review:
      summary: Interaction with transferrin (TF) and hephaestin (HEPH) in iron 
        release complex.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0005102
          label: signaling receptor binding
      supported_by:
        - reference_id: PMID:37277838
          supporting_text: Apo- and holo-transferrin differentially interact 
            with hephaestin and ferroportin in a novel mechanism of cellular 
            iron release regulation.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IDA
    original_reference_id: PMID:29237594
    review:
      summary: Direct demonstration of hepcidin binding to ferroportin with 
        structure-function analysis.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:29237594
          supporting_text: 2017 Dec 13. Structure-function analysis of 
            ferroportin defines the binding site and an alternative mechanism of
            action of hepcidin.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:29792530
    review:
      summary: Basolateral localization in polarized hepatocyte model (WIF-B 
        cells).
      action: ACCEPT
      reason: Thompson et al. demonstrated ferroportin localization to the 
        basolateral membrane of polarized WIF-B hepatocytes, consistent with its
        role in hepatic iron export.
      supported_by:
        - reference_id: PMID:29792530
          supporting_text: Manganese transport and toxicity in polarized WIF-B 
            hepatocytes.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:30247984
    review:
      summary: Plasma membrane localization demonstrated in disease mutation 
        study.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30247984
          supporting_text: Ferroportin disease mutations influence manganese 
            accumulation and cytotoxicity.
  - term:
      id: GO:0005381
      label: iron ion transmembrane transporter activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Iron transporter activity from sequence similarity to mouse 
        ferroportin.
      action: ACCEPT
      reason: Human and mouse ferroportin are highly conserved and functionally 
        equivalent. This ISS annotation is well-supported.
  - term:
      id: GO:0015093
      label: ferrous iron transmembrane transporter activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Ferrous iron transporter activity from mouse ortholog similarity.
      action: ACCEPT
      reason: Supported by direct experimental evidence (IDA from PMID:15692071)
        and conserved function in mouse.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Basolateral localization from mouse ortholog similarity.
      action: ACCEPT
      reason: Well-supported by multiple IDA annotations and consistent with 
        polarized epithelial cell biology.
  - term:
      id: GO:0060586
      label: multicellular organismal-level iron ion homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Systemic iron homeostasis annotation from mouse ortholog.
      action: ACCEPT
      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.
  - term:
      id: GO:0017046
      label: peptide hormone binding
    evidence_type: IPI
    original_reference_id: PMID:22682227
    review:
      summary: Hepcidin binding demonstrated in ubiquitination study.
      action: ACCEPT
      reason: Qiao et al. showed that hepcidin binding to ferroportin triggers 
        ubiquitination at lysine residues, leading to endocytosis and 
        degradation.
      supported_by:
        - reference_id: PMID:22682227
          supporting_text: Hepcidin-induced endocytosis of ferroportin is 
            dependent on ferroportin ubiquitination.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5655733
    review:
      summary: Plasma membrane annotation from Reactome pathway for defective 
        SLC40A1.
      action: ACCEPT
      reason: Reactome pathway curation correctly places ferroportin at the 
        plasma membrane.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5655760
    review:
      summary: Plasma membrane annotation from Reactome pathway.
      action: ACCEPT
      reason: Consistent with established localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:20019163
    review:
      summary: Plasma membrane localization from hephaestin co-localization 
        study.
      action: ACCEPT
      reason: Hudson et al. demonstrated ferroportin plasma membrane 
        localization in various tissues including duodenum and pancreatic 
        beta-cells.
      supported_by:
        - reference_id: PMID:20019163
          supporting_text: 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.
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:20019163
    review:
      summary: Basolateral localization from same hephaestin study.
      action: ACCEPT
      reason: Direct demonstration of basolateral ferroportin localization.
      supported_by:
        - reference_id: PMID:20019163
          supporting_text: 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.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-442368
    review:
      summary: Reactome annotation for iron transport reaction.
      action: ACCEPT
      reason: Reactome pathway R-HSA-442368 describes SLC40A1:HEPH:6Cu2+ 
        transporting Fe2+ from cytosol to extracellular region, correctly 
        placing ferroportin at the plasma membrane.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5621402
    review:
      summary: Reactome annotation for ceruloplasmin deficiency pathway.
      action: ACCEPT
      reason: Correct localization in Reactome iron metabolism pathways.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-904830
    review:
      summary: Reactome annotation for iron transport with ceruloplasmin.
      action: ACCEPT
      reason: Correct localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917891
    review:
      summary: Reactome annotation for iron oxidation reaction.
      action: ACCEPT
      reason: Correct localization in Reactome iron oxidation pathway.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917933
    review:
      summary: Reactome annotation for hephaestin-mediated iron oxidation.
      action: ACCEPT
      reason: Correct localization.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IC
    original_reference_id: PMID:12091367
    review:
      summary: Plasma membrane localization inferred from iron transporter 
        function.
      action: ACCEPT
      reason: Curator inference from demonstrated iron transporter activity. 
        Supported by direct experimental evidence.
      supported_by:
        - reference_id: PMID:12091367
          supporting_text: Autosomal dominant reticuloendothelial iron overload 
            associated with a 3-base pair deletion in the ferroportin 1 gene 
            (SLC11A3).
  - term:
      id: GO:0005381
      label: iron ion transmembrane transporter activity
    evidence_type: IMP
    original_reference_id: PMID:12091367
    review:
      summary: Iron transporter activity from mutant phenotype analysis.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:12091367
          supporting_text: Autosomal dominant reticuloendothelial iron overload 
            associated with a 3-base pair deletion in the ferroportin 1 gene 
            (SLC11A3).
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: IMP
    original_reference_id: PMID:12091367
    review:
      summary: Intracellular iron homeostasis role from genetic evidence.
      action: ACCEPT
      reason: Mutations in ferroportin disrupt cellular iron homeostasis, 
        causing iron retention in macrophages and other cells. This is a core 
        function.
      supported_by:
        - reference_id: PMID:12091367
          supporting_text: Autosomal dominant reticuloendothelial iron overload 
            associated with a 3-base pair deletion in the ferroportin 1 gene 
            (SLC11A3).
  - term:
      id: GO:0034755
      label: iron ion transmembrane transport
    evidence_type: IMP
    original_reference_id: PMID:12091367
    review:
      summary: Iron transmembrane transport from genetic evidence.
      action: ACCEPT
      reason: The disease phenotype demonstrates ferroportin's essential role in
        iron transmembrane transport.
      supported_by:
        - reference_id: PMID:12091367
          supporting_text: Autosomal dominant reticuloendothelial iron overload 
            associated with a 3-base pair deletion in the ferroportin 1 gene 
            (SLC11A3).
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000054
    review:
      summary: Plasma membrane localization from fusion protein localization 
        studies.
      action: ACCEPT
      reason: Direct experimental evidence from LIFEdb localization studies.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: TAS
    original_reference_id: PMID:10747949
    review:
      summary: Cytoplasm annotation from early discovery paper.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:10747949
          supporting_text: A novel mammalian iron-regulated protein involved in 
            intracellular iron metabolism.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: TAS
    original_reference_id: PMID:10747949
    review:
      summary: Generic membrane annotation from early discovery paper.
      action: ACCEPT
      reason: Ferroportin is an integral membrane protein. This broad annotation
        is accurate, though more specific annotations (plasma membrane, 
        basolateral membrane) are more informative.
      supported_by:
        - reference_id: PMID:10747949
          supporting_text: A novel mammalian iron-regulated protein involved in 
            intracellular iron metabolism.
core_functions:
  - molecular_function:
      id: GO:0015093
      label: ferrous iron transmembrane transporter activity
    description: Ferroportin is the sole known mammalian iron exporter. It 
      specifically transports ferrous iron (Fe2+) from the cytoplasm to the 
      extracellular space via an electroneutral 2H+/Fe2+ antiport mechanism. 
      This function has been demonstrated by direct transport assays in Xenopus 
      oocytes and mammalian cells (PMID:15692071, PMID:24304836), cryo-EM 
      structural analysis revealing iron-binding sites (PMID:32814342), and 
      genetic evidence from hemochromatosis type 4 patients (PMID:12091367).
  - molecular_function:
      id: GO:0017046
      label: peptide hormone binding
    description: Ferroportin directly binds the peptide hormone hepcidin (HAMP),
      which is the master regulator of systemic iron homeostasis. Hepcidin 
      binding blocks iron transport and triggers ferroportin ubiquitination and 
      degradation. Structural studies have mapped the hepcidin-binding site 
      (PMID:29237594, PMID:32814342). Iron binding to ferroportin increases 
      hepcidin affinity ~80-fold, ensuring hepcidin preferentially targets 
      iron-loaded ferroportin.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000054
    title: Gene Ontology annotation based on curation of intracellular 
      localizations of expressed fusion proteins in living cells
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10747949
    title: A novel mammalian iron-regulated protein involved in intracellular 
      iron metabolism.
    findings:
      - statement: Original discovery of MTP1/ferroportin identifying it as an 
          iron-regulated protein involved in iron metabolism.
        supporting_text: We have isolated and characterized a novel 
          iron-regulated gene that is homologous to the divalent metal 
          transporter 1 family of metal transporters
  - id: PMID:10882071
    title: A novel duodenal iron-regulated transporter, IREG1, implicated in the
      basolateral transfer of iron to the circulation.
    findings:
      - statement: Identified IREG1 (ferroportin) at the basolateral membrane of
          duodenal enterocytes
        supporting_text: We describe here the isolation and characterization of 
          a novel cDNA (Ireg1) encoding a duodenal protein that is localized to 
          the basolateral membrane of polarized epithelial cells
      - statement: Implicated in transfer of dietary iron to the circulation
        supporting_text: We conclude that IREG1 represents the long-sought 
          duodenal iron export protein
  - id: PMID:12091367
    title: Autosomal dominant reticuloendothelial iron overload associated with 
      a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).
    findings:
      - statement: V162del mutation causes hemochromatosis type 4
        supporting_text: A 3-base pair deletion in exon 5 of the ferroportin 1 
          gene (SLC11A3) predicting Val162 deletion was found in affected 
          members
      - statement: Established genetic evidence for ferroportin role in iron 
          export
        supporting_text: These results indicate that this extracellular cluster 
          is functionally important for iron transport, and its disruption leads
          to iron overload
  - id: PMID:15692071
    title: In vitro functional analysis of human ferroportin (FPN) and 
      hemochromatosis-associated FPN mutations.
    findings:
      - statement: Demonstrated ferrous iron (Fe2+) transport activity
        supporting_text: expression of human FPN in a human cell line results in
          an iron deficiency because of a 3-fold increased export of iron
      - statement: Characterized disease mutations A77D and G490D showing loss 
          of function
        supporting_text: FPN mutations A77D, V162delta, and G490D that are 
          associated with a typical pattern of disease in vivo cause a loss of 
          iron export function in vitro
  - id: PMID:20019163
    title: 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.
    findings:
      - statement: Co-localization of ferroportin with hephaestin
        supporting_text: In addition to its expression in the same cells as Hp, 
          ferroportin was also localized to the ductal cells of the exocrine 
          pancreas
      - statement: Basolateral membrane localization in multiple tissues
        supporting_text: previous immunocytochemical studies in rat, mouse, and 
          human gut tissues localized Hp to the basolateral membranes of the 
          duodenal enterocytes
  - id: PMID:20817278
    title: "Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited
      by zinc in Alzheimer's disease."
    findings:
      - statement: APP interacts with ferroportin to facilitate iron export
        supporting_text: Like ceruloplasmin, APP catalytically oxidizes Fe(2+), 
          loads Fe(3+) into transferrin, and has a major interaction with 
          ferroportin
  - id: PMID:22682227
    title: Hepcidin-induced endocytosis of ferroportin is dependent on 
      ferroportin ubiquitination.
    findings:
      - statement: Hepcidin binding triggers ferroportin ubiquitination
        supporting_text: Hepcidin binding caused rapid ubiquitination of 
          ferroportin in cell lines overexpressing ferroportin and in murine 
          bone marrow-derived macrophages
      - statement: Ubiquitination required for endocytosis and degradation
        supporting_text: Our study demonstrates that ubiquitination is the 
          functionally relevant signal for hepcidin-induced ferroportin 
          endocytosis
  - id: PMID:24867889
    title: sAPP modulates iron efflux from brain microvascular endothelial cells
      by stabilizing the ferrous iron exporter ferroportin.
    findings:
      - statement: Soluble APP stabilizes ferroportin at the membrane
        supporting_text: "the stimulation of efflux supported by this peptide and
          by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin
          (Fpn), in the plasma membrane"
      - statement: Mechanism of iron export regulation in brain
        supporting_text: in stabilizing Fpn via the targeting due to the FTP 
          sequence, sAPP will increase the flux of iron into the cerebral 
          interstitium
  - id: PMID:29237594
    title: Structure-function analysis of ferroportin defines the binding site 
      and an alternative mechanism of action of hepcidin.
    findings:
      - statement: Mapped hepcidin binding site on ferroportin
        supporting_text: hepcidin binding occurred within the central cavity of 
          Fpn
      - statement: Identified key residues N144, Y501, D504 required for binding
        supporting_text: All clinical mutants were functionally resistant to 
          hepcidin as a consequence of either impaired hepcidin binding or 
          impaired hepcidin-dependent ubiquitination despite intact hepcidin 
          binding
      - statement: N144D shows complete loss of hepcidin binding
        supporting_text: mutations that caused ubiquitination-resistance were 
          positioned at helix-helix interfaces, likely preventing the 
          hepcidin-induced conformational change
  - id: PMID:29792530
    title: Manganese transport and toxicity in polarized WIF-B hepatocytes.
    findings:
      - statement: Ferroportin localized to basolateral membrane in hepatocytes
        supporting_text: Fpn and ZIP14 localize to basolateral domains
      - statement: Evidence that Mn2+ is not a physiological substrate
        supporting_text: Hepcidin reduced levels of Fpn in WIF-B cells, clearing
          Fpn from the cell surface, but Mn efflux was unaffected
  - id: PMID:30247984
    title: Ferroportin disease mutations influence manganese accumulation and 
      cytotoxicity.
    findings:
      - statement: Characterized disease mutations affecting localization and 
          function
        supporting_text: disease mutations interfere with the role of Fpn in 
          controlling Mn levels as well as the stability of Fpn
      - statement: G80S, D157G lose cell surface localization
        supporting_text: Hemochromatosis is a frequent genetic disorder, 
          characterized by the accumulation of excess iron across tissues
      - statement: N144H/T show hepcidin resistance
        supporting_text: These results define the function of Fpn as an exporter
          of both iron and Mn
  - id: PMID:32814342
    title: Structure of hepcidin-bound ferroportin reveals iron homeostatic 
      mechanisms.
    findings:
      - statement: Cryo-EM structure of ferroportin with and without hepcidin
        supporting_text: determine cryogenic electron microscopy structures of 
          ferroportin in lipid nanodiscs, both in the apo state and in complex 
          with hepcidin and the iron mimetic cobalt
      - statement: Revealed iron-binding sites and hepcidin binding as molecular
          cork
        supporting_text: Hepcidin binds ferroportin in an outward-open 
          conformation and completely occludes the iron efflux pathway
      - statement: 12-TM topology confirmed
        supporting_text: hepcidin directly contacts the divalent metal in the 
          ferroportin C domain
  - id: PMID:37277838
    title: Apo- and holo-transferrin differentially interact with hephaestin and
      ferroportin in a novel mechanism of cellular iron release regulation.
    findings:
      - statement: Ferroportin, hephaestin, and transferrin form functional 
          complex
        supporting_text: holo-Tf directly interacts with ferroportin, whereas 
          apo-Tf directly interacts with hephaestin
      - statement: Holo-transferrin promotes ferroportin degradation
        supporting_text: We demonstrate that holo-Tf induces the internalization
          of ferroportin through the established ferroportin degradation pathway
  - id: Reactome:R-HSA-442368
    title: SLC40A1:HEPH:6Cu2+ transports Fe2+ from cytosol to extracellular 
      region
    findings: []
  - id: Reactome:R-HSA-5621402
    title: Defective CP does not oxidise Fe2+ to Fe3+
    findings: []
  - id: Reactome:R-HSA-5655733
    title: Defective SLC40A1 does not transport Fe2+ from cytosol to 
      extracellular region
    findings: []
  - id: Reactome:R-HSA-5655760
    title: Defective SLC40A1 does not transport Fe3+ from extracellular region 
      to cytosol
    findings: []
  - id: Reactome:R-HSA-904830
    title: SLC40A1:CP:6Cu2+ transports Fe2+ from cytosol to extracellular region
    findings: []
  - id: Reactome:R-HSA-917891
    title: SLC40A1:CP:6Cu2+ oxidises Fe2+ to Fe3+
    findings: []
  - id: Reactome:R-HSA-917933
    title: SLC40A1:HEPH:6Cu2+ oxidises 4Fe2+ to 4Fe3+
    findings: []
tags:
  - ferroptosis

SLC40A1

Gene Description

Existing Annotations Review

Core Functions

References

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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

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If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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