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
Author Information
Fabian Hoelzgen: The Kreitman School of Advanced Graduate Studies, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Thuy T P Nguyen: Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Elina Klukin: Department of Life Sciences, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Mohamed Boumaiza: Department of Chemistry, State University of New York at Potsdam (SUNY Potsdam), Potsdam, NY, USA.
Ayush K Srivastava: Department of Chemistry, State University of New York at Potsdam (SUNY Potsdam), Potsdam, NY, USA.
Elizabeth Y Kim: Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ran Zalk: Ilse Katz Institute for Nanoscale Science & Technology, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel. ORCID
Anat Shahar: Ilse Katz Institute for Nanoscale Science & Technology, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Sagit Cohen-Schwartz: The National Institute for Biotechnology in the Negev - NIBN, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Esther G Meyron-Holtz: Faculty of Biotechnology and Food Engineering, Technion, Haifa, Israel.
Fadi Bou-Abdallah: Department of Chemistry, State University of New York at Potsdam (SUNY Potsdam), Potsdam, NY, USA. ORCID
Joseph D Mancias: 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. ORCID
Gabriel A Frank: Department of Life Sciences, Marcus Family Campus, Ben-Gurion University of the Negev, Beer-Sheva, Israel. frankg@bgu.ac.il. ORCID
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.
References
Cancer Discov. 2022 Sep 2;12(9):2180-2197
[PMID: 35771492]
