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Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
AB. Loveland, E. Svidritskiy, D. Susorov, S. Lee, A. Park, S. Zvornicanin, G. Demo, FB. Gao, AA. Korostelev
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
R01 NS101986
NINDS NIH HHS - United States
R35 GM127094
NIGMS NIH HHS - United States
R01 GM107465
NIGMS NIH HHS - United States
R37 NS057553
NINDS NIH HHS - United States
Free Medical Journals od 2010
Nature Open Access od 2010-12-01
PubMed Central od 2012
Europe PubMed Central od 2012
ProQuest Central od 2010-01-01
Open Access Digital Library od 2015-01-01
Open Access Digital Library od 2015-01-01
Medline Complete (EBSCOhost) od 2012-11-01
Health & Medicine (ProQuest) od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources od 2010
Odkazy
PubMed
35589706
DOI
10.1038/s41467-022-30418-0
Knihovny.cz E-zdroje
- MeSH
- amyotrofická laterální skleróza * genetika metabolismus MeSH
- dipeptidy metabolismus MeSH
- elektronová kryomikroskopie MeSH
- frontotemporální demence * genetika metabolismus MeSH
- lidé MeSH
- protein C9orf72 genetika metabolismus MeSH
- proteiny genetika metabolismus MeSH
- ribozomy metabolismus MeSH
- transferasy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Toxic dipeptide-repeat (DPR) proteins are produced from expanded G4C2 repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.
Central European Institute of Technology Masaryk University Kamenice 5 Brno 625 00 Czech Republic
Department of Neurology UMass Chan Medical School 368 Plantation Street Worcester MA 01605 USA
RNA Therapeutics Institute UMass Chan Medical School 368 Plantation Street Worcester MA 01605 USA
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