Proteomics

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Arginine valency in C9ORF72 dipolypeptides mediates promiscuous proteome binding that transmits multiple modes of toxicity


ABSTRACT: C9ORF72-associated Motor Neuron Disease patients feature abnormal expression of 5 dipeptide repeat (DPR) polymers. Here we used quantitative proteomics in a mouse neuronal-like cell line (Neuro2a) to demonstrate that the valency of Arg in the most toxic DPRS, PR and GR, drives promiscuous binding to the proteome, compared to a relative sparse binding of the more inert AP and GA. Notable targets included ribosomal proteins, translation initiation factors and translation elongation factors. PR and GR comprising more than 10 repeats robustly stalled the ribosome suggesting high-valency Arg electrostatically jams the ribosome exit tunnel during synthesis. Poly-GR also bound to arginine methylases and induced hypomethylation of endogenous proteins, with a profound destabilization of the actin cytoskeleton. Our findings point to arginine in GR and PR polymers as multivalent toxins to translation as well as arginine methylation with concomitant downstream effects on widespread biological processes including ribosome biogenesis, mRNA splicing and cytoskeleton assembly.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Mona Radwan  

LAB HEAD: Prof. Danny Hatters

PROVIDER: PXD015180 | Pride | 2020-02-25

REPOSITORIES: Pride

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Publications

Arginine in <i>C9ORF72</i> Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity.

Radwan Mona M   Ang Ching-Seng CS   Ormsby Angelique R AR   Cox Dezerae D   Daly James C JC   Reid Gavin E GE   Hatters Danny M DM  

Molecular & cellular proteomics : MCP 20200221 4


<i>C9ORF72</i>-associated Motor Neuron Disease patients feature abnormal expression of 5 dipeptide repeat (DPR) polymers. Here we used quantitative proteomics in a mouse neuronal-like cell line (Neuro2a) to demonstrate that the Arg residues in the most toxic DPRS, PR and GR, leads to a promiscuous binding to the proteome compared with a relative sparse binding of the more inert AP and GA. Notable targets included ribosomal proteins, translation initiation factors and translation elongation facto  ...[more]

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