Structural highlights
Publication Abstract from PubMed
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.
Structural basis for the intracellular regulation of ferritin degradation.,Hoelzgen F, Nguyen TTP, Klukin E, Boumaiza M, Srivastava AK, Kim EY, Zalk R, Shahar A, Cohen-Schwartz S, Meyron-Holtz EG, Bou-Abdallah F, Mancias JD, Frank GA Nat Commun. 2024 May 7;15(1):3802. doi: 10.1038/s41467-024-48151-1. PMID:38714719[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hoelzgen F, Nguyen TTP, Klukin E, Boumaiza M, Srivastava AK, Kim EY, Zalk R, Shahar A, Cohen-Schwartz S, Meyron-Holtz EG, Bou-Abdallah F, Mancias JD, Frank GA. Structural basis for the intracellular regulation of ferritin degradation. Nat Commun. 2024 May 7;15(1):3802. PMID:38714719 doi:10.1038/s41467-024-48151-1
