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-Structure paper
タイトル | Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 2776, Year 2022 |
掲載日 | 2022年5月19日 |
著者 | Anna B Loveland / Egor Svidritskiy / Denis Susorov / Soojin Lee / Alexander Park / Sarah Zvornicanin / Gabriel Demo / Fen-Biao Gao / Andrei A Korostelev / |
PubMed 要旨 | 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). ...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. |
リンク | Nat Commun / PubMed:35589706 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.4 - 3.1 Å |
構造データ | EMDB-26033, PDB-7too: EMDB-26034, PDB-7top: EMDB-26035, PDB-7toq: EMDB-26036, PDB-7tor: EMDB-26037, PDB-7tos: |
化合物 | ChemComp-ZN: |
由来 |
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キーワード | RIBOSOME (リボソーム) / Ribosomal binding peptide / ALS/FTD-associated dipeptide repeat protein |