Proteomics

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


ABSTRACT: Motor Neuron Disease patients with the C9ORF72 hexanucleotide expansion mutations feature abnormal expression of 5 different dipeptide repeat polymers (DPRs). Two of these, poly-GR and poly-PR, have proven highly toxic to cell and animal models. To investigate the mechanisms, we defined the interactomes of the DPRs in 10× and 101× repeat lengths as fusions to GFP in Neuro2a cells using quantitative proteomics. Relative to the more inert poly-GA and poly-PA peptides, poly-PR and poly-GR of both repeat lengths were promiscuous binders to the proteome and especially ribosomal proteins, translation initiation factors and translation elongation factors including ribosome recycling factor ABCE1, suggesting a role in ribosome stalling. The PR101 and GR101 DPRs robustly stalled the ribosome compared to the other DPRs and an unrelated mutant protein (Huntingtin) that causes neurodegeneration. Poly-GR also bound to arginine methylases and led to hypomethylation of endogenous proteins, with a profound destabilization of the actin cytoskeleton. Our findings point to arginine in the 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: PXD015177 | Pride | 2020-02-25

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Pulldown-AP.pdResult Other
Pulldown-AP.pep.xml Pepxml
Pulldown-AP.prot.xml Xml
Pulldown-AP_R1.msf Msf
Pulldown-AP_R1.raw Raw
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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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