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- PDB-8qu9: Structure of the NCOA4 (Nuclear Receptor Coactivator 4)-FTH1 (H-F... -

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Basic information

Entry
Database: PDB / ID: 8qu9
TitleStructure of the NCOA4 (Nuclear Receptor Coactivator 4)-FTH1 (H-Ferritin) complex
Components
  • Ferritin heavy chain
  • NCOA4 (Nuclear Receptor Coactivator 4)
KeywordsMETAL TRANSPORT / Ferritinophagy / Iron homeostasis / NCOA4 / Ferritin heavy chain
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 / negative regulation of fibroblast proliferation / ferric iron binding ...iron ion sequestering activity / ferritin complex / Scavenging by Class A Receptors / negative regulation of ferroptosis / Golgi Associated Vesicle Biogenesis / ferroxidase / autolysosome / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding / autophagosome / iron ion transport / Iron uptake and transport / ferrous iron binding / tertiary granule lumen / ficolin-1-rich granule lumen / intracellular iron ion homeostasis / immune response / iron ion binding / negative regulation of cell population proliferation / Neutrophil degranulation / extracellular exosome / extracellular region / identical protein binding / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsHoelzgen, F. / Klukin, E. / Zalk, R. / Shahar, A. / Cohen-Schwartz, S. / Frank, G.A.
Funding support United States, 2items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
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Revision 1.1Feb 19, 2025Group: Data collection / Derived calculations / Structure summary
Category: em_admin / pdbx_entry_details ...em_admin / pdbx_entry_details / pdbx_struct_assembly_gen / pdbx_struct_oper_list
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ferritin heavy chain
B: NCOA4 (Nuclear Receptor Coactivator 4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7534
Polymers22,6412
Non-polymers1122
Water181
1
A: Ferritin heavy chain
B: NCOA4 (Nuclear Receptor Coactivator 4)
hetero molecules
x 24


Theoretical massNumber of molelcules
Total (without water)546,07096
Polymers543,38948
Non-polymers2,68148
Water43224
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation23

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Components

#1: Protein Ferritin heavy chain


Mass: 20764.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FTH1 / Production host: Escherichia coli (E. coli) / References: UniProt: P02794
#2: Protein/peptide NCOA4 (Nuclear Receptor Coactivator 4)


Mass: 1877.122 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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

ComponentName: FTH1 NCOA4 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 30 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 49794 / Symmetry type: POINT

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