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; Gabriel A Frank

doi:10.1038/s41467-024-48151-1

Structural basis for the intracellular regulation of ferritin degradation

Nat Commun. 2024 May 7;15(1):3802. doi: 10.1038/s41467-024-48151-1.

Authors

Fabian Hoelzgen^#^{1

2}, Thuy T P Nguyen^#³, Elina Klukin², Mohamed Boumaiza⁴, Ayush K Srivastava⁴, Elizabeth Y Kim³, Ran Zalk⁵, Anat Shahar⁵, Sagit Cohen-Schwartz⁶, Esther G Meyron-Holtz⁷, Fadi Bou-Abdallah⁴, Joseph D Mancias^{8

9}, Gabriel A Frank^{10

11

12}

Affiliations

¹ The Kreitman School of Advanced Graduate Studies, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
² Department of Life Sciences, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
³ Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Department of Chemistry, State University of New York at Potsdam (SUNY Potsdam), Potsdam, NY, USA.
⁵ Ilse Katz Institute for Nanoscale Science & Technology, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁶ The National Institute for Biotechnology in the Negev - NIBN, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁷ Faculty of Biotechnology and Food Engineering, Technion, Haifa, Israel.
⁸ Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Joseph_Mancias@dfci.harvard.edu.
⁹ Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Joseph_Mancias@dfci.harvard.edu.
¹⁰ Department of Life Sciences, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel. frankg@bgu.ac.il.
¹¹ Ilse Katz Institute for Nanoscale Science & Technology, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel. frankg@bgu.ac.il.
¹² The National Institute for Biotechnology in the Negev - NIBN, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel. frankg@bgu.ac.il.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Binding Sites
Cryoelectron Microscopy*
Ferritins* / chemistry
Ferritins* / genetics
Ferritins* / metabolism
HEK293 Cells
Humans
Iron / metabolism
Models, Molecular
Mutation
Nuclear Receptor Coactivators* / chemistry
Nuclear Receptor Coactivators* / genetics
Nuclear Receptor Coactivators* / metabolism
Oxidoreductases / chemistry
Oxidoreductases / genetics
Oxidoreductases / metabolism
Protein Binding
Proteolysis

Substances

Ferritins
FTH1 protein, human
Nuclear Receptor Coactivators
NCOA4 protein, human
Iron
Oxidoreductases

Grants and funding

R01 DK124384/DK/NIDDK NIH HHS/United States