Scientists use new chemoproteomic method for global profiling of arginine dimethylation

By The Science Advisory Board staff writers

October 20, 2022 -- Protein arginine methylation plays an important role in regulating protein functions in different cellular processes, and its dysregulation may lead to a variety of diseases. A study published October 18 in the journal Proceedings of the National Academy of Sciences has revealed how arginine dimethylation regulates protein liquid-liquid phase separation (LLPS) and membraneless organelles (MLOs) by using a new chemoproteomic method.

Arginine residue can be modified with a cis-diol group by reacting with vicinal dicarbonyl compound, which enables the enrichment of arginine-containing peptides by boronate-affinity chromatography. In their study, the research team led by Ye Mingliang, PhD, from the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences (CAS), in collaboration with Liu Cong, PhD, from the Shanghai Institute of Organic Chemistry of CAS, found that the modifications of some groups on arginine residue could severely influence this reaction.

The researchers developed a steric effect-based chemical enrichment method (SECEM), which could enrich arginine dimethylated peptides from a complex peptide mixture for proteomics analysis. They found this method could increase the identification performance of arginine demethylation (DMA) at the proteome level. Using SECEM, they discovered that in mammalian cells the DMA sites occurring in the RG/RGG motifs were enriched within the proteins identified in different MLOs, especially stress granules (SGs).

Moreover, further global profiling of the arginine DMA dynamic change upon SG formation by SECEM identified that the most dramatic change of arginine dimethylation occurred at multiple sites of RG/RGG-rich regions from several key SG-contained proteins, including G3BP1, FUS, hnRNPA1, and KHDRBS1.

Notably, in vitro arginine methylation and mutation of dimethylated arginine site impaired LLPS capability of these RG/RGG-rich regions, which further validated the important role of DMA in regulating protein LLPS, according to the researchers.

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