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Title | Structural basis for the intracellular regulation of ferritin degradation. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 3802, Year 2024 |
Publish date | May 7, 2024 |
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 / |
PubMed 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. |
External links | Nat Commun / PubMed:38714719 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.88 Å |
Structure data | EMDB-18658, PDB-8qu9: |
Chemicals | ChemComp-FE: ChemComp-HOH: |
Source |
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Keywords | METAL TRANSPORT / Ferritinophagy / Iron homeostasis / NCOA4 / Ferritin heavy chain |