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- PDB-6wbv: Structure of human ferroportin bound to hepcidin and cobalt in li... -

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Basic information

Entry
Database: PDB / ID: 6wbv
TitleStructure of human ferroportin bound to hepcidin and cobalt in lipid nanodisc
Components
  • Fab45D8 Heavy Chain
  • Fab45D8 Light Chain
  • Hepcidin
  • Solute carrier family 40 member 1
KeywordsTRANSLOCASE/IMMUNE SYSTEM/HORMONE / ferroportin / transporter / iron / hepcidin / TRANSLOCASE-IMMUNE SYSTEM-HORMONE complex
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 / iron ion transmembrane transport / lymphocyte homeostasis / iron ion transmembrane transporter activity ...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 / iron ion transmembrane transport / lymphocyte homeostasis / iron ion transmembrane transporter activity / 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 / peptide hormone binding / cell surface receptor signaling pathway via JAK-STAT / 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 / killing of cells of another organism / intracellular iron ion homeostasis / 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 / membrane / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Hepcidin / Hepcidin / Ferroportin-1 / Ferroportin1 (FPN1) / MFS transporter superfamily
Similarity search - Domain/homology
Chem-AGA / : / Hepcidin / Solute carrier family 40 member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsBillesboelle, C.B. / Azumaya, C.M. / Gonen, S. / Powers, A. / Kretsch, R.C. / Schneider, S. / Arvedson, T. / Dror, R.O. / Cheng, Y. / Manglik, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1DP5OD023048 United States
CitationJournal: 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
DepositionMar 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
B: Hepcidin
A: Solute carrier family 40 member 1
L: Fab45D8 Light Chain
H: Fab45D8 Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,0428
Polymers117,0134
Non-polymers1,0294
Water19811
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9280 Å2
ΔGint-76 kcal/mol
Surface area37730 Å2

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Components

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Protein , 2 types, 2 molecules AH

#2: Protein Solute carrier family 40 member 1 / Ferroportin-1 / Iron-regulated transporter 1


Mass: 66349.898 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC40A1, FPN1, IREG1, SLC11A3, MSTP079 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NP59, Translocases
#4: Protein Fab45D8 Heavy Chain


Mass: 23852.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Protein/peptide / Antibody , 2 types, 2 molecules BL

#1: Protein/peptide Hepcidin / / Liver-expressed antimicrobial peptide 1 / LEAP-1 / Putative liver tumor regressor / PLTR


Mass: 2802.455 Da / Num. of mol.: 1 / Fragment: UNP residues 60-84 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P81172
#3: Antibody Fab45D8 Light Chain


Mass: 24008.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Non-polymers , 3 types, 15 molecules

#5: Chemical ChemComp-AGA / (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PENTANOYLOXY)METHYL]ETHYL OCTANOATE / PHOSPHATIDYL GLYCEROL


Mass: 455.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H36O10P
#6: Chemical ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Co / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Ferroportin-Fab45D8 complexCOMPLEX#1-#40MULTIPLE SOURCES
2Ferroportin-hepcidin complexCOMPLEX#1-#21RECOMBINANT
3Fab45D8COMPLEX#3-#41RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: -20000 nm / Nominal defocus min: -8000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 66 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 3 / Num. of real images: 5415
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4CTFFINDCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12RELIONclassification
13cisTEM3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 310647 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047005
ELECTRON MICROSCOPYf_angle_d0.8369547
ELECTRON MICROSCOPYf_dihedral_angle_d19.0232439
ELECTRON MICROSCOPYf_chiral_restr0.0471124
ELECTRON MICROSCOPYf_plane_restr0.0061176

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