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TitleRibosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 2776, Year 2022
Publish dateMay 19, 2022
AuthorsAnna B Loveland / Egor Svidritskiy / Denis Susorov / Soojin Lee / Alexander Park / Sarah Zvornicanin / Gabriel Demo / Fen-Biao Gao / Andrei A Korostelev /
PubMed AbstractToxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ...Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC 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.
External linksNat Commun / PubMed:35589706 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 3.1 Å
Structure data

26033

7too

EMDB-26033, PDB-7too:
Yeast 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20
Method: EM (single particle) / Resolution: 2.7 Å

26034

7top

EMDB-26034, PDB-7top:
Yeast 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein PR20
Method: EM (single particle) / Resolution: 2.4 Å

26035

7toq

EMDB-26035, PDB-7toq:
Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein poly-PR
Method: EM (single particle) / Resolution: 3.1 Å

26036

7tor

EMDB-26036, PDB-7tor:
Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20
Method: EM (single particle) / Resolution: 2.9 Å

26037

7tos

EMDB-26037, PDB-7tos:
E. coli 70S ribosomes bound with the ALS/FTD-associated dipeptide repeat protein PR20
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • baker's yeast (brewer's yeast)
  • escherichia coli (E. coli)
  • homo sapiens (human)
  • saccharomyces cerevisiae (brewer's yeast)
  • oryctolagus cuniculus (rabbit)
  • escherichia coli k-12 (bacteria)
  • rabbit (rabbit)
KeywordsRIBOSOME / Ribosomal binding peptide / ALS/FTD-associated dipeptide repeat protein

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