PXD015177

PXD015177 is an original dataset announced via ProteomeXchange.

Title	Arginine valency in C9ORF72 dipolypeptides mediates promiscuous proteome binding that transmits multiple modes of toxicity
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:00:16.218.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mona Radwan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-27 07:11:32	ID requested
1	2020-02-25 10:21:30	announced
2	2020-02-27 23:01:35	announced	2020-02-28: Updated publication reference for PubMed record(s): 32086375.
⏵ 3	2024-10-22 05:00:24	announced	2024-10-22: Updated project metadata.

Radwan M, Ang CS, Ormsby AR, Cox D, Daly JC, Reid GE, Hatters DM, Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity. Mol Cell Proteomics, 19(4):640-654(2020) [pubmed]

10.1074/mcp.ra119.001888;

submitter keyword: RAN-translation

Amyotrophic Lateral Sclerosis (ALS)

proteotoxicity

protein aggregation

ABCE1

methylosome

PRMT1

PRMT5

Prof. Danny Hatters
contact affiliation	NHMRC Senior Research Fellow Department of Biochemistry and Molecular Biology | Faculty of Medicine, Dentistry and Health Sciences Level 2 South, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road The University of Melbourne, Victoria 3010 Australia
contact email	dhatters@unimelb.edu.au
lab head
Mona Radwan
contact affiliation	PhD student
contact email	monar@student.unimelb.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/02/PXD015177

PRIDE project URI

• PRIDE
  1. PXD015177
     1. Label: PRIDE project
     2. Name: Arginine valency in C9ORF72 dipolypeptides mediates promiscuous proteome binding that transmits multiple modes of toxicity