- EMDB-18658: Structure of the NCOA4 (Nuclear Receptor Coactivator 4)-FTH1 (H-F... -
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Entry
Database: EMDB / ID: EMD-18658
Title
Structure 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
Keywords
Ferritinophagy / Iron homeostasis / NCOA4 / Ferritin heavy chain / METAL TRANSPORT
Function / homology
Function and homology information
iron ion sequestering activity / : / autolysosome / Scavenging by Class A Receptors / Golgi Associated Vesicle Biogenesis / ferroxidase / intracellular sequestering of iron ion / ferroxidase activity / negative regulation of fibroblast proliferation / ferric iron binding ...iron ion sequestering activity / : / autolysosome / Scavenging by Class A Receptors / Golgi Associated Vesicle Biogenesis / ferroxidase / intracellular sequestering of iron ion / ferroxidase activity / negative regulation of fibroblast proliferation / 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 / iron ion binding / immune response / negative regulation of cell population proliferation / Neutrophil degranulation / extracellular exosome / extracellular region / identical protein binding / membrane / nucleus / cytoplasm / cytosol Similarity search - Function
United States - Israel Binational Science Foundation (BSF)
#2022614
United States
National Science Foundation (NSF, United States)
2231900
United States
Citation
Journal: 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.
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