Hutten, Saskia;
Chen, Jia-Xuan;
Isaacs, Adrian M;
Dormann, Dorothee;
(2024)
Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink.
Biochemistry
, 63
(17)
pp. 2141-2152.
10.1021/acs.biochem.4c00308.
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Hutten at al_revised_final.pdf - Accepted Version Access restricted to UCL open access staff until 16 August 2025. Download (1MB) |
Abstract
Dipeptide repeat proteins (DPRs) are aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases characterized by the cytoplasmic mislocalization and aggregation of RNA-binding proteins (RBPs). In particular, arginine (R)-rich DPRs (poly-GR and poly-PR) have been suggested to promiscuously interact with multiple cellular proteins and thereby exert high cytotoxicity. Components of the protein arginine methylation machinery have been identified as modulators of DPR toxicity and/or potential cellular interactors of R-rich DPRs; however, the molecular details and consequences of such an interaction are currently not well understood. Here, we demonstrate that several members of the family of protein arginine methyltransferases (PRMTs) can directly interact with R-rich DPRs in vitro and in the cytosol. In vitro, R-rich DPRs reduce solubility and promote phase separation of PRMT1, the main enzyme responsible for asymmetric arginine-dimethylation (ADMA) in mammalian cells, in a concentration- and length-dependent manner. Moreover, we demonstrate that poly-GR interferes more efficiently than poly-PR with PRMT1-mediated arginine methylation of RBPs such as hnRNPA3. We additionally show by two alternative approaches that poly-GR itself is a substrate for PRMT1-mediated arginine dimethylation. We propose that poly-GR may act as a direct competitor for arginine methylation of cellular PRMT1 targets, such as disease-linked RBPs.
| Type: | Article |
|---|---|
| Title: | Poly-GR Impairs PRMT1-Mediated Arginine Methylation of Disease-Linked RNA-Binding Proteins by Acting as a Substrate Sink |
| Location: | United States |
| DOI: | 10.1021/acs.biochem.4c00308 |
| Publisher version: | https://doi.org/10.1021/acs.biochem.4c00308 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | ALS, Biochemistry & Molecular Biology, C9ORF72, GGGGCC REPEAT, HEXANUCLEOTIDE REPEAT EXPANSION, IDENTIFICATION, Life Sciences & Biomedicine, METHYLTRANSFERASE PRMT1, NUCLEAR IMPORT, PHASE-SEPARATION, Science & Technology, STRESS, TOXICITY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203357 |
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