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- PDB-6w4s: Structure of apo human ferroportin in lipid nanodisc -

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Basic information

Entry
Database: PDB / ID: 6w4s
TitleStructure of apo human ferroportin in lipid nanodisc
Components
  • Fab45D8 Heavy Chain
  • Fab45D8 Light Chain
  • Solute carrier family 40 member 1
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / ferroportin / transporter / iron / hepcidin / TRANSPORT PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


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 ...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 / peptide hormone binding / establishment of localization in cell / Iron uptake and transport / multicellular organismal-level iron ion homeostasis / synaptic vesicle / basolateral plasma membrane / intracellular iron ion homeostasis / transcription by RNA polymerase II / apoptotic process / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / nucleoplasm / membrane / identical protein binding / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Ferroportin-1 / Ferroportin1 (FPN1) / MFS transporter superfamily
Similarity search - Domain/homology
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: 3.2 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 11, 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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Structure viewerMolecule:
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Assembly

Deposited unit
F: Solute carrier family 40 member 1
H: Fab45D8 Heavy Chain
L: Fab45D8 Light Chain


Theoretical massNumber of molelcules
Total (without water)114,2113
Polymers114,2113
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2980 Å2
ΔGint-21 kcal/mol
Surface area28610 Å2

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Components

#1: 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
#2: 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)
#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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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 complexCOMPLEXall0MULTIPLE SOURCES
2FerroportinCOMPLEX#11RECOMBINANT
3Fab45D8COMPLEX#2-#31RECOMBINANT
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
SpecimenEmbedding 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: 60 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 308366 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045101
ELECTRON MICROSCOPYf_angle_d0.5436952
ELECTRON MICROSCOPYf_dihedral_angle_d20.898698
ELECTRON MICROSCOPYf_chiral_restr0.039824
ELECTRON MICROSCOPYf_plane_restr0.004849

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