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- EMDB-18658: Structure of the NCOA4 (Nuclear Receptor Coactivator 4)-FTH1 (H-F... -

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Basic information

Entry
Database: EMDB / ID: EMD-18658
TitleStructure of the NCOA4 (Nuclear Receptor Coactivator 4)-FTH1 (H-Ferritin) complex
Map data
Sample
  • Complex: FTH1 NCOA4 complex
    • Protein or peptide: Ferritin heavy chain
    • Protein or peptide: NCOA4 (Nuclear Receptor Coactivator 4)
  • Ligand: FE (III) ION
  • Ligand: water
KeywordsFerritinophagy / Iron homeostasis / NCOA4 / Ferritin heavy chain / METAL TRANSPORT
Function / homology
Function and homology information


iron ion sequestering activity / ferritin complex / Scavenging by Class A Receptors / negative regulation of ferroptosis / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / intracellular sequestering of iron ion / negative regulation of fibroblast proliferation ...iron ion sequestering activity / ferritin complex / Scavenging by Class A Receptors / negative regulation of ferroptosis / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / intracellular sequestering of iron ion / negative regulation of fibroblast proliferation / autophagosome / ferric iron binding / Iron uptake and transport / ferrous iron binding / tertiary granule lumen / iron ion transport / intracellular iron ion homeostasis / ficolin-1-rich granule lumen / immune response / iron ion binding / negative regulation of cell population proliferation / Neutrophil degranulation / extracellular exosome / extracellular region / identical protein binding / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Ferritin iron-binding regions signature 1. / Ferritin iron-binding regions signature 2. / Ferritin, conserved site / Ferritin / Ferritin-like diiron domain / Ferritin-like diiron domain profile. / Ferritin/DPS protein domain / Ferritin-like domain / Ferritin-like / Ferritin-like superfamily
Similarity search - Domain/homology
Ferritin heavy chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsHoelzgen F / Klukin E / Zalk R / Shahar A / Cohen-Schwartz S / Frank GA
Funding support United States, 2 items
OrganizationGrant numberCountry
United States - Israel Binational Science Foundation (BSF)#2022614 United States
National Science Foundation (NSF, United States)2231900 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for the intracellular regulation of ferritin degradation.
Authors: Fabian Hoelzgen / Thuy T P Nguyen / Elina Klukin / Mohamed Boumaiza / Ayush K Srivastava / Elizabeth Y Kim / Ran Zalk / Anat Shahar / Sagit Cohen-Schwartz / Esther G Meyron-Holtz / Fadi Bou- ...Authors: Fabian Hoelzgen / Thuy T P Nguyen / Elina Klukin / Mohamed Boumaiza / Ayush K Srivastava / Elizabeth Y Kim / Ran Zalk / Anat Shahar / Sagit Cohen-Schwartz / Esther G Meyron-Holtz / Fadi Bou-Abdallah / Joseph D Mancias / Gabriel A Frank /
Abstract: The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ...The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy-a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4-FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.
History
DepositionOct 15, 2023-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18658.png

Downloads & links

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Map

FileDownload / File: emd_18658.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 256 pix.
= 227.84 Å		0.89 Å/pix.
x 256 pix.
= 227.84 Å		0.89 Å/pix.
x 256 pix.
= 227.84 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.89 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0113
Minimum - Maximum-0.040212482 - 0.083434194
Average (Standard dev.)0.0003981855 (±0.004661681)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 227.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_18658_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_18658_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : FTH1 NCOA4 complex

EntireName: FTH1 NCOA4 complex
Components
  • Complex: FTH1 NCOA4 complex
    • Protein or peptide: Ferritin heavy chain
    • Protein or peptide: NCOA4 (Nuclear Receptor Coactivator 4)
  • Ligand: FE (III) ION
  • Ligand: water

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Supramolecule #1: FTH1 NCOA4 complex

SupramoleculeName: FTH1 NCOA4 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Ferritin heavy chain

MacromoleculeName: Ferritin heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.764098 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TSQVRQNYHQ DSEAAINRQI NLELYASYVY LSMSYYFDRD DVALKNFAKY FLHQSHEERE HAEKLMKLQN QRGGRIFLQD IKKPDCDDW ESGLNAMECA LHLEKNVNQS LLELHKLATD KNDPHLCDFI ETHYLNEQVK AIKELGDHVT NLRKMGAPES G LAEYLFDK HTLGDSDNES

UniProtKB: Ferritin heavy chain

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Macromolecule #2: NCOA4 (Nuclear Receptor Coactivator 4)

MacromoleculeName: NCOA4 (Nuclear Receptor Coactivator 4) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.877122 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DSFQVIKNSP LSEWLI

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Macromolecule #3: FE (III) ION

MacromoleculeName: FE (III) ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: FE
Molecular weightTheoretical: 55.845 Da

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 130000
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7rrp

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 49794
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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