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Yorodumi- EMDB-21599: Structure of human ferroportin bound to hepcidin and cobalt in li... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-21599 | |||||||||
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Title | Structure of human ferroportin bound to hepcidin and cobalt in lipid nanodisc | |||||||||
Map data | human ferroportin bound to hepcidin and cobalt in lipid nanodisc | |||||||||
Sample |
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Function / homology | Function and homology information negative regulation of intestinal absorption / spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport ...negative regulation of intestinal absorption / spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport / ferrous iron transmembrane transporter activity / endothelium development / macrophage activation / positive regulation of macrophage activation / response to iron ion / negative regulation of bone resorption / negative regulation of iron ion transmembrane transport / myeloid cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / peptide hormone binding / defense response to fungus / establishment of localization in cell / Iron uptake and transport / protein catabolic process / hormone activity / multicellular organismal-level iron ion homeostasis / negative regulation of inflammatory response / positive regulation of protein catabolic process / synaptic vesicle / basolateral plasma membrane / intracellular iron ion homeostasis / killing of cells of another organism / transcription by RNA polymerase II / defense response to bacterium / inflammatory response / immune response / copper ion binding / apoptotic process / negative regulation of apoptotic process / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / nucleoplasm / identical protein binding / membrane / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Billesboelle CB / Azumaya CM / Gonen S / Powers A / Kretsch RC / Schneider S / Arvedson T / Dror RO / Cheng Y / Manglik A | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nature / Year: 2020 Title: Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Authors: Christian B Billesbølle / Caleigh M Azumaya / Rachael C Kretsch / Alexander S Powers / Shane Gonen / Simon Schneider / Tara Arvedson / Ron O Dror / Yifan Cheng / Aashish Manglik / Abstract: 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 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 ferroportin. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias. 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. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21599.map.gz | 95.6 MB | EMDB map data format | |
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Header (meta data) | emd-21599-v30.xml emd-21599.xml | 22.5 KB 22.5 KB | Display Display | EMDB header |
Images | emd_21599.png | 92.2 KB | ||
Others | emd_21599_half_map_1.map.gz emd_21599_half_map_2.map.gz | 37.4 MB 37.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21599 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21599 | HTTPS FTP |
-Validation report
Summary document | emd_21599_validation.pdf.gz | 769.9 KB | Display | EMDB validaton report |
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Full document | emd_21599_full_validation.pdf.gz | 769.5 KB | Display | |
Data in XML | emd_21599_validation.xml.gz | 13.4 KB | Display | |
Data in CIF | emd_21599_validation.cif.gz | 15.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21599 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21599 | HTTPS FTP |
-Related structure data
Related structure data | 6wbvMC 6w4sC 6w4vC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21599.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | human ferroportin bound to hepcidin and cobalt in lipid nanodisc | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: #1
File | emd_21599_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_21599_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Ferroportin-Fab45D8 complex
+Supramolecule #1: Ferroportin-Fab45D8 complex
+Supramolecule #2: Ferroportin-hepcidin complex
+Supramolecule #3: Fab45D8
+Macromolecule #1: Hepcidin
+Macromolecule #2: Solute carrier family 40 member 1
+Macromolecule #3: Fab45D8 Light Chain
+Macromolecule #4: Fab45D8 Heavy Chain
+Macromolecule #5: (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-...
+Macromolecule #6: COBALT (II) ION
+Macromolecule #7: water
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 1.5 mg/mL |
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Buffer | pH: 7.5 |
Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 3 / Number real images: 5415 / Average exposure time: 6.0 sec. / Average electron dose: 66.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -20.0 µm / Nominal defocus min: -8.0 µm / Nominal magnification: 105000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |