Structural basis for the intracellular regulation of ferritin degradation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
14
11
2023
accepted:
19
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38714719
doi: 10.1038/s41467-024-48151-1
pii: 10.1038/s41467-024-48151-1
doi:
Substances chimiques
Ferritins
9007-73-2
FTH1 protein, human
EC 1.-
Nuclear Receptor Coactivators
0
NCOA4 protein, human
0
Iron
E1UOL152H7
Oxidoreductases
EC 1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3802Subventions
Organisme : Israel Science Foundation (ISF)
ID : 364/20
Organisme : United States - Israel Binational Science Foundation (BSF)
ID : 2022614
Organisme : National Science Foundation (NSF)
ID : 2231900
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01-DK124384
Informations de copyright
© 2024. The Author(s).
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