PXD015180

PXD015180 is an original dataset announced via ProteomeXchange.

Title	Arginine valency in C9ORF72 dipolypeptides mediates promiscuous proteome binding that transmits multiple modes of toxicity
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-02-25
AnnouncementXML	Submission_2020-02-27_23:02:45.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 07:39:35	ID requested
1	2020-02-25 12:06:21	announced
⏵ 2	2020-02-27 23:02:46	announced	2020-02-28: Updated publication reference for PubMed record(s): 32086375.

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]

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/PXD015180

PRIDE project URI

• PRIDE
  1. PXD015180
     1. Label: PRIDE project
     2. Name: Arginine valency in C9ORF72 dipolypeptides mediates promiscuous proteome binding that transmits multiple modes of toxicity