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

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

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4 Scopus citations

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.

Original language	English
Article number	3802
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-48151-1
State	Published - 1 Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Hoelzgen, F., Nguyen, T. T. P., Klukin, E., Boumaiza, M., Srivastava, A. K., Kim, E. Y., Zalk, R., Shahar, A., Cohen-Schwartz, S., Meyron-Holtz, E. G., Bou-Abdallah, F., Mancias, J. D., & Frank, G. A. (2024). Structural basis for the intracellular regulation of ferritin degradation. Nature Communications, 15(1), Article 3802. https://doi.org/10.1038/s41467-024-48151-1

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title = "Structural basis for the intracellular regulation of ferritin degradation",

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.",

author = "Fabian Hoelzgen and Nguyen, {Thuy T.P.} and Elina Klukin and Mohamed Boumaiza and Srivastava, {Ayush K.} and Kim, {Elizabeth Y.} and Ran Zalk and Anat Shahar and Sagit Cohen-Schwartz and Meyron-Holtz, {Esther G.} and Fadi Bou-Abdallah and Mancias, {Joseph D.} and Frank, {Gabriel A.}",

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AU - Nguyen, Thuy T.P.

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AU - Boumaiza, Mohamed

AU - Srivastava, Ayush K.

AU - Kim, Elizabeth Y.

AU - Zalk, Ran

AU - Shahar, Anat

AU - Cohen-Schwartz, Sagit

AU - Meyron-Holtz, Esther G.

AU - Bou-Abdallah, Fadi

AU - Mancias, Joseph D.

AU - Frank, Gabriel A.

PY - 2024/12/1

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N2 - 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.

AB - 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.

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Structural basis for the intracellular regulation of ferritin degradation

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