Structural basis for the intracellular regulation of ferritin degradation

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 () and Gabriel A. Frank ()
Additional contact information
Fabian Hoelzgen: Ben-Gurion University of the Negev
Thuy T. P. Nguyen: Harvard Medical School
Elina Klukin: Ben-Gurion University of the Negev
Mohamed Boumaiza: State University of New York at Potsdam (SUNY Potsdam)
Ayush K. Srivastava: State University of New York at Potsdam (SUNY Potsdam)
Elizabeth Y. Kim: Harvard Medical School
Ran Zalk: Ben-Gurion University of the Negev
Anat Shahar: Ben-Gurion University of the Negev
Sagit Cohen-Schwartz: Ben-Gurion University of the Negev
Esther G. Meyron-Holtz: Technion
Fadi Bou-Abdallah: State University of New York at Potsdam (SUNY Potsdam)
Joseph D. Mancias: Harvard Medical School
Gabriel A. Frank: Ben-Gurion University of the Negev

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-024-48151-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48151-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-48151-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().