Key result
Poly-PR and poly-GR proteins block the polypeptide tunnel of the ribosome at nanomolar concentrations, inhibiting peptidyl-transferase activity and revealing the structural basis of their toxicity.
Why the study?
Poly-PR and poly-GR dipeptide repeat proteins cause cellular translation repression in C9ORF72-associated ALS and FTD, but the underlying molecular mechanism remains unknown.
Poly-PR and poly-GR proteins associated with C9ORF72-ALS/FTD inhibit cellular translation by strongly and specifically binding to the ribosomal polypeptide tunnel, revealing the structural basis of their toxicity.
Poly-PR/GR inhibit peptidyl-transferase; hypothesis-generating for C9ORF72 toxicity, requires validation before any therapeutic consideration.
Toxic dipeptide repeat (DPR) proteins are produced from expanded G 4 C 2 hexanucleotide repeats in the C9ORF72 gene, which cause 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 cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins 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.
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Loveland et al. (2020) studied Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). poly-PR and poly-GR proteins was evaluated on Ribosome peptidyl-transferase activity and structural binding. Poly-PR and poly-GR proteins block the polypeptide tunnel of the ribosome at nanomolar concentrations, inhibiting peptidyl-transferase activity and revealing the structural basis of their toxicity.
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