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Structural basis for the intracellular regulation of ferritin degradation

Author

Listed:
  • Fabian Hoelzgen

    (Ben-Gurion University of the Negev
    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
    Harvard Medical School)

  • Gabriel A. Frank

    (Ben-Gurion University of the Negev
    Ben-Gurion University of the Negev
    Ben-Gurion University of the Negev)

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.

Suggested Citation

  • 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-Abdal, 2024. "Structural basis for the intracellular regulation of ferritin degradation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48151-1
    DOI: 10.1038/s41467-024-48151-1
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    References listed on IDEAS

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    1. Masahiro Yoshida & Shunsuke Minagawa & Jun Araya & Taro Sakamoto & Hiromichi Hara & Kazuya Tsubouchi & Yusuke Hosaka & Akihiro Ichikawa & Nayuta Saito & Tsukasa Kadota & Nahoko Sato & Yusuke Kurita & , 2019. "Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Joseph D. Mancias & Xiaoxu Wang & Steven P. Gygi & J. Wade Harper & Alec C. Kimmelman, 2014. "Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy," Nature, Nature, vol. 509(7498), pages 105-109, May.
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