Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and
poly-GR proteins revealed by cryo-EM

J 2022

Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK et. al.

Základní údaje

Originální název

Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

Autoři

LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK, Sarah ZVORNICANIN, Gabriel DEMO (703 Slovensko, garant, domácí), Fen-Biao GAO a Andrei A KOROSTELEV

Vydání

Nature Communications, London, Nature Publishing Group, 2022, 2041-1723

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 16.600

Kód RIV

RIV/00216224:14740/22:00127474

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1038/s41467-022-30418-0

UT WoS

000798347800050

Klíčová slova anglicky

Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cryoelectron Microscopy; Dipeptides; Frontotemporal Dementia; Humans; Proteins; Ribosomes; Transferases

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 12. 2022 13:38, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

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.

Citovat

LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK, Sarah ZVORNICANIN, Gabriel DEMO, Fen-Biao GAO a Andrei A KOROSTELEV. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Nature Communications. London: Nature Publishing Group, 2022, roč. 13, č. 1, s. 2776-2788. ISSN 2041-1723. Dostupné z: https://dx.doi.org/10.1038/s41467-022-30418-0.

@article{2240099,
   author = {Loveland, Anna B and Svidritskiy, Egor and Susorov, Denis and Lee, Soojin and Park, Alexander and Zvornicanin, Sarah and Demo, Gabriel and Gao, FenandBiao and Korostelev, Andrei A},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41467-022-30418-0},
   keywords = {Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cryoelectron Microscopy; Dipeptides; Frontotemporal Dementia; Humans; Proteins; Ribosomes; Transferases},
   language = {eng},
   issn = {2041-1723},
   journal = {Nature Communications},
   title = {Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM},
   url = {https://www.nature.com/articles/s41467-022-30418-0},
   volume = {13},
   year = {2022}
}

TY  - JOUR
ID  - 2240099
AU  - Loveland, Anna B - Svidritskiy, Egor - Susorov, Denis - Lee, Soojin - Park, Alexander - Zvornicanin, Sarah - Demo, Gabriel - Gao, Fen-Biao - Korostelev, Andrei A
PY  - 2022
TI  - Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
JF  - Nature Communications
VL  - 13
IS  - 1
SP  - 2776
EP  - 2776
PB  - Nature Publishing Group
SN  - 20411723
KW  - Amyotrophic Lateral Sclerosis
KW  - C9orf72 Protein
KW  - Cryoelectron Microscopy
KW  - Dipeptides
KW  - Frontotemporal Dementia
KW  - Humans
KW  - Proteins
KW  - Ribosomes
KW  - Transferases
UR  - https://www.nature.com/articles/s41467-022-30418-0
N2  - 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.
ER  -

LOVELAND, Anna B, Egor SVIDRITSKIY, Denis SUSOROV, Soojin LEE, Alexander PARK, Sarah ZVORNICANIN, Gabriel DEMO, Fen-Biao GAO a Andrei A KOROSTELEV. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. \textit{Nature Communications}. London: Nature Publishing Group, 2022, roč.~13, č.~1, s.~2776-2788. ISSN~2041-1723. Dostupné z: https://dx.doi.org/10.1038/s41467-022-30418-0.

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