SART3 reads methylarginine-marked glycine- and arginine-rich motifs

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114459
• Main Authors: Wang, Yalong, Zhou, Jujun, He, Wei, Fu, Rongjie, Shi, Leilei, Dang, Ngoc Khoi, Liu, Bin, Xu, Han, Cheng, Xiaodong, Bedford, Mark T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-07-2024; Elsevier
• Subjects: Amino Acid Motifs; Arginine - chemistry; Arginine - metabolism; arginine methylation; Chromosomal Proteins, Non-Histone - chemistry; Chromosomal Proteins, Non-Histone - metabolism; CP: Molecular biology; Glycine - chemistry; Glycine - metabolism; HEK293 Cells; Humans; Methylation; Protein Binding; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - metabolism; RNA Splicing; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; SART3; TPR domain; CP: Molecular biology; TPR domain; SART3; arginine methylation; RNA splicing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114459

Glycine- and arginine-rich (GAR) motifs, commonly found in RNA-binding and -processing proteins, can be symmetrically (SDMA) or asymmetrically (ADMA) dimethylated at the arginine residue by protein arginine methyltransferases. Arginine-methylated protein motifs are usually read by Tudor domain-containing proteins. Here, using a GFP-Trap, we identify a non-Tudor domain protein, squamous cell carcinoma antigen recognized by T cells 3 (SART3), as a reader for SDMA-marked GAR motifs. Structural analysis and mutagenesis of SART3 show that aromatic residues lining a groove between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains are essential for SART3 to recognize and bind to SDMA-marked GAR motif peptides, as well as for the interaction between SART3 and the GAR-motif-containing proteins fibrillarin and coilin. Further, we show that the loss of this reader ability affects RNA splicing. Overall, our findings broaden the range of potential SDMA readers to include HAT domains.
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•SART3 is a methylarginine reader•The HAT repeat domain of SART3 harbors reader function•Reader activity is implicated in the regulation of RNA splicing
Using a composite arginine methylation substrate, Wang et al. identify SART3 as a “reader” of symmetrically dimethylated arginine (SDMA) motifs. This binding is mediated by a groove formed between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains. The integrity of this methyl-dependent interaction is required for normal splicing.