Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ceruloplasmin-ferroportin system of iron traffic in vertebrates.

ABSTRACT: Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin (SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasmin-ferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.

SUBMITTER: Musci G

PROVIDER: S-EPMC4050113 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Ceruloplasmin-ferroportin system of iron traffic in vertebrates.

Musci Giovanni G Polticelli Fabio F Bonaccorsi di Patti Maria Carmela MC

World journal of biological chemistry 20140501 2

Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin (SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iro ...[more]

PMID: 24921009

Similar Datasets

Astrocyte-derived hepcidin controls iron traffic at the blood-brain-barrier via regulating ferroportin 1 of microvascular endothelial cells.

Project description:Brain iron dysregulation associated with aging is closely related to motor and cognitive impairments in neurodegenerative diseases. The regulation of iron traffic at the blood-brain barrier (BBB) is crucial to maintain brain iron homeostasis. However, the specific mechanism has not been clarified in detail. Using various conditional gene knockout and overexpression mice, as well as cell co-culture of astrocyte and bEND.3 in the transwell, we found that astrocyte hepcidin knockdown increased the expression of ferroportin 1 (FPN1) of brain microvascular endothelial cells (BMVECs), and that it also induced brain iron overload and cognitive decline in mice. Moreover, BMVECs FPN1 knockout decreased iron contents in the cortex and hippocampus. Furthermore, hepcidin regulates the level of FPN1 of BMVECs with conditional gene overexpression in vivo and in vitro. Our results revealed that astrocytes responded to the intracellular high iron level and increased the secretion of hepcidin, which in turn diminished iron uptake at BBB from circulation through directly regulating FPN1 of BMVECs. Our results demonstrate that FPN1 of BMVECs is a gateway for iron transport into the brain from circulation, and the controller of this gateway is hepcidin secreted by astrocyte at its endfeet through physical contact with BMVECs. This regulation is indeed the major checkpoint for iron transport from the blood circulation to the brain. This study delineates the pathway and regulation of iron entry into the brain, providing potential therapeutic targets for iron dysregulation-related neurological diseases.

| S-EPMC9343463 | biostudies-literature

Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin.

Project description:Ferroportin (Fpn), a ferrous iron Fe(II) transporter responsible for the entry of iron into plasma, is regulated post-translationally through internalization and degradation following binding of the hormone hepcidin. Cellular iron export is impaired in mice and humans with aceruloplasminemia, an iron overload disease due to mutations in the ferroxidase ceruloplasmin (Cp). In the absence of Cp Fpn is rapidly internalized and degraded. Depletion of extracellular Fe(II) by the yeast ferroxidase Fet3p or iron chelators can maintain cell surface Fpn in the absence of Cp. Iron remains bound to Fpn in the absence of multicopper oxidases. Fpn with bound iron is recognized by a ubiquitin ligase, which ubiquitinates Fpn on lysine 253. Mutation of lysine 253 to alanine prevents ubiquitination and maintains Fpn-iron on cell surface in the absence of ferroxidase activity. The requirement for a ferroxidase to maintain iron transport activity represents a new mechanism of regulating cellular iron export, a new function for Cp and an explanation for brain iron overload in patients with aceruloplasminemia.

| S-EPMC1894773 | biostudies-literature

Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease.

Project description:Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder.

| S-EPMC5478206 | biostudies-literature

Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins.

Project description:Copper-containing ferroxidase ceruloplasmin (Cp) forms binary and ternary complexes with cationic proteins lactoferrin (Lf) and myeloperoxidase (Mpo) during inflammation. We present an X-ray crystal structure of a 2Cp-Mpo complex at 4.7 Å resolution. This structure allows one to identify major protein-protein interaction areas and provides an explanation for a competitive inhibition of Mpo by Cp and for the activation of p-phenylenediamine oxidation by Mpo. Small angle X-ray scattering was employed to construct low-resolution models of the Cp-Lf complex and, for the first time, of the ternary 2Cp-2Lf-Mpo complex in solution. The SAXS-based model of Cp-Lf supports the predicted 1:1 stoichiometry of the complex and demonstrates that both lobes of Lf contact domains 1 and 6 of Cp. The 2Cp-2Lf-Mpo SAXS model reveals the absence of interaction between Mpo and Lf in the ternary complex, so Cp can serve as a mediator of protein interactions in complex architecture. Mpo protects antioxidant properties of Cp by isolating its sensitive loop from proteases. The latter is important for incorporation of Fe(3+) into Lf, which activates ferroxidase activity of Cp and precludes oxidation of Cp substrates. Our models provide the structural basis for possible regulatory role of these complexes in preventing iron-induced oxidative damage.

| S-EPMC3700992 | biostudies-literature

Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin.

Project description:Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5' untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-responsive mechanism for the post-transcriptional regulation of FPN, mediated by miR-485-3p, which is induced during iron deficiency and represses FPN expression by directly targeting the FPN 3'UTR. The overexpression of miR-485-3p represses FPN expression and leads to increased cellular ferritin levels, consistent with increased cellular iron. Conversely, both inhibition of miR-485-3p activity and mutation of the miR-485-3p target sites on the FPN 3'UTR are able to relieve FPN repression and lead to decreased cellular iron levels. Together, these findings support a model that includes both IRPs and microRNAs as iron-responsive post-transcriptional regulators of FPN. The involvement of microRNA in the iron-responsive regulation of FPN offers additional stability and fine-tuning of iron homeostasis within different cellular contexts. MiR-485-3p-mediated repression of FPN may also offer a novel potential therapeutic mechanism for circumventing hepcidin-resistant mechanisms responsible for some iron overload diseases.

| S-EPMC3616902 | biostudies-literature

Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.

Project description:The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin1. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias2. Here we 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. These structures and accompanying molecular dynamics simulations identify two metal-binding sites within the N and C domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy terminus of hepcidin directly contacts the divalent metal in the ferroportin C domain. Hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, in which only ferroportin molecules loaded with iron are targeted for degradation. More broadly, our structural and functional insights may enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.

| S-EPMC7906036 | biostudies-literature

Human ferroportin mediates proton-coupled active transport of iron.

Project description:As the sole iron exporter in humans, ferroportin controls systemic iron homeostasis through exporting iron into the blood plasma. The molecular mechanism of how ferroportin exports iron under various physiological settings remains unclear. Here we found that purified ferroportin incorporated into liposomes preferentially transports Fe2+ and exhibits lower affinities of transporting other divalent metal ions. The iron transport by ferroportin is facilitated by downhill proton gradients at the same direction. Human ferroportin is also capable of transporting protons, and this activity is tightly coupled to the iron transport. Remarkably, ferroportin can conduct active transport uphill against the iron gradient, with favorable charge potential providing the driving force. Targeted mutagenesis suggests that the iron translocation site is located at the pore region of human ferroportin. Together, our studies enhance the mechanistic understanding by which human ferroportin transports iron and suggest that a combination of electrochemical gradients regulates iron export.

| S-EPMC7556139 | biostudies-literature

Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux.

Project description:Iron efflux from mammalian cells is supported by the synergistic actions of the ferrous iron efflux transporter, ferroportin (Fpn) and a multicopper ferroxidase, that is, hephaestin (Heph), ceruloplasmin (Cp) or both. The two proteins stabilize Fpn in the plasma membrane and catalyze extracellular Fe3+ release. The membrane stabilization of Fpn is also stimulated by its interaction with a 22-amino acid synthetic peptide based on a short sequence in the extracellular E2 domain of the amyloid precursor protein (APP). However, whether APP family members interact with Fpn in vivo is unclear. Here, using cyan fluorescent protein (CFP)-tagged Fpn in conjunction with yellow fluorescent protein (YFP) fusions of Heph and APP family members APP, APLP1, and APLP2 in HEK293T cells we used fluorescence and surface biotinylation to quantify Fpn membrane occupancy and also measured 59Fe efflux. We demonstrate that Fpn and Heph co-localize, and FRET analysis indicated that the two proteins form an iron-efflux complex. In contrast, none of the full-length, cellular APP proteins exhibited Fpn co-localization or FRET. Moreover, iron supplementation increased surface expression of the iron-efflux complex, and copper depletion knocked down Heph activity and decreased Fpn membrane localization. Whereas cellular APP species had no effects on Fpn and Heph localization, addition of soluble E2 elements derived from APP and APLP2, but not APLP1, increased Fpn membrane occupancy. We conclude that a ferroportin-targeting sequence, (K/R)EWEE, present in APP and APLP2, but not APLP1, helps modulate Fpn-dependent iron efflux in the presence of an active multicopper ferroxidase.

| S-EPMC6422103 | biostudies-literature

Iron Export through the Transporter Ferroportin 1 Is Modulated by the Iron Chaperone PCBP2.

Project description:Ferroportin 1 (FPN1) is an iron export protein found in mammals. FPN1 is important for the export of iron across the basolateral membrane of absorptive enterocytes and across the plasma membrane of macrophages. The expression of FPN1 is regulated by hepcidin, which binds to FPN1 and then induces its degradation. Previously, we demonstrated that divalent metal transporter 1 (DMT1) interacts with the intracellular iron chaperone protein poly(rC)-binding protein 2 (PCBP2). Subsequently, PCBP2 receives iron from DMT1 and then disengages from the transporter. In this study, we investigated the function of PCBP2 in iron export. Mammalian genomes encode four PCBPs (i.e. PCBP1-4). Here, for the first time, we demonstrated using both yeast and mammalian cells that PCBP2, but not PCBP1, PCBP3, or PCBP4, binds with FPN1. Importantly, iron-loaded, but not iron-depleted, PCBP2 interacts with FPN1. The PCBP2-binding domain of FPN1 was identified in its C-terminal cytoplasmic region. The silencing of PCBP2 expression suppressed FPN1-dependent iron export from cells. These results suggest that FPN1 exports iron received from the iron chaperone PCBP2. Therefore, it was found that PCBP2 modulates cellular iron export, which is an important physiological process.

| S-EPMC5016129 | biostudies-literature

Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease.

Project description:Growing body of evidence suggests that Parkinson's disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). Low ceruloplasmin (CP)-ferroxidase activity has been identified in the SN and the cerebrospinal fluid (CSF) of patients with PD. The iron chelator, deferiprone, reduces the abnormally high levels of iron in the SN. In order to determine CP's involvement in iron accumulation in SN and PD progression, we aim to compare the ability of iron chelation treatment to reducing both SN iron levels and motor handicap in PD patients according to the level of ceruloplasmin activity.We used a moderate chelation protocol with deferiprone (DFP) based on a, 6-month delayed-start paradigm, randomized placebo controlled clinical trial in 40 PD patients. CP-ferroxidase activity was determined in blood and CSF together with the D544E gene polymorphism (rs701753). Iron levels were determined by R2* MRI sequence and the motor handicap by the UPDRS motor score.After 6 to 12 months of DFP treatment, greater reductions in SN iron levels and UPDRS motor scores were obtained in patients with higher serum and CSF levels of CP-ferroxidase activity. After 6 months of DFP treatment, the AT genotype group displayed greater reduction of iron level in the SN with greater CSF and serum levels of CP activity than the AA genotype group.Although most of the DFP-treated patients displayed clinical and radiological improvements, those with the lower CP activity appeared to respond better to iron chelation. Larger RCTs are now needed to establish whether pharmacological modulation of CP activity could be an innovative neuroprotective strategy in PD.FAIR-PARK study (ClinicalTrials.gov reference: NCT00943748 ; French national reference number: 2008-006842-25). This study was approved by the French Drug Agency (ANSM) and the local institutional review board ("Comité de Protection des Personnes of Lille").

| S-EPMC4429376 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data