Research ResourcePosttranslational Modifications

Proteome-wide analysis of arginine monomethylation reveals widespread occurrence in human cells

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Science Signaling  30 Aug 2016:
Vol. 9, Issue 443, pp. rs9
DOI: 10.1126/scisignal.aaf7329

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Appreciating arginine methylation

Posttranslational modifications, such as phosphorylation and ubiquitylation, regulate protein abundance, localization, interactions, and function. Larsen et al. investigated the landscape and functional roles of the posttranslational modification arginine methylation. RNA interference and high-throughput single-cell imaging revealed that arginine methylation regulated two proteins involved in RNA processing and transport. Arginine methylation by distinct arginine methyltransferases controlled the localization and RNA binding functions of the pre-mRNA splicing factor SRSF2 and the RNA-transporting activity of the protein HNRNPUL1. On a broader level, their data provide a rich resource for the future investigation of the function of arginine methylation and indicate that sites modified by this posttranslational modification are hotspots for mutations in disease.


The posttranslational modification of proteins by arginine methylation is functionally important, yet the breadth of this modification is not well characterized. Using high-resolution mass spectrometry, we identified 8030 arginine methylation sites within 3300 human proteins in human embryonic kidney 293 cells, indicating that the occurrence of this modification is comparable to phosphorylation and ubiquitylation. A site-level conservation analysis revealed that arginine methylation sites are less evolutionarily conserved compared to arginines that were not identified as modified by methylation. Through quantitative proteomics and RNA interference to examine arginine methylation stoichiometry, we unexpectedly found that the protein arginine methyltransferase (PRMT) family of arginine methyltransferases catalyzed methylation independently of arginine sequence context. In contrast to the frequency of somatic mutations at arginine methylation sites throughout the proteome, we observed that somatic mutations were common at arginine methylation sites in proteins involved in mRNA splicing. Furthermore, in HeLa and U2OS cells, we found that distinct arginine methyltransferases differentially regulated the functions of the pre-mRNA splicing factor SRSF2 (serine/arginine-rich splicing factor 2) and the RNA transport ribonucleoprotein HNRNPUL1 (heterogeneous nuclear ribonucleoprotein U-like 1). Knocking down PRMT5 impaired the RNA binding function of SRSF2, whereas knocking down PRMT4 [also known as coactivator-associated arginine methyltransferase 1 (CARM1)] or PRMT1 increased the RNA binding function of HNRNPUL1. High-content single-cell imaging additionally revealed that knocking down CARM1 promoted the nuclear accumulation of SRSF2, independent of cell cycle phase. Collectively, the presented human arginine methylome provides a missing piece in the global and integrative view of cellular physiology and protein regulation.

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