Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants
| Autor: | Chen Sun, Kunpeng Li, Ruben Vidal, Bernardino Ghetti, Wen Jiang, Barry B. Muhoberac, Jose Irimia-Dominguez, Holly J. Garringer, G.I. Hallinan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cryo-electron microscopy Polymers Iron Neuroaxonal Dystrophies lcsh:Medicine Article 03 medical and health sciences 0302 clinical medicine medicine Homeostasis Humans lcsh:Science Gene Multidisciplinary biology Chemistry lcsh:R Neurodegeneration Cryoelectron Microscopy Brain Neurodegenerative Diseases Metabolism Alzheimer's disease medicine.disease Iron Metabolism Disorders In vitro Cell biology Ferritin Ferritin light chain 030104 developmental biology Neurology Apoferritins Mutation biology.protein lcsh:Q 030217 neurology & neurosurgery Function (biology) Neurological disorders |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) |
| ISSN: | 2045-2322 |
| Popis: | The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin’s three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin’s iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF. |
| Databáze: | OpenAIRE |
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