Protein methylation is a critical post-translational modification that plays an essential role in numerous physiological processes. While arginine and lysine methylation have been widely studied, the methylation of other amino acids has remained underexplored due to the lack of effective analytical methods.
In a study published in Nature Communications, teams led by Prof. CHENG Hong from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, in collaboration with Prof. YE Mingliang and Prof. LI Guohui from the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences, and Prof. WANG Zefeng from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, developed an innovative protein methylation analysis technique that provides a comprehensive view of the necessity of histidine methylation in maintaining the structure of C3H1 zinc fingers. The research also discovered that histidine methylation plays a crucial auxiliary role in U2AF1’s recognition of the 3’ splice site and exon splicing, expanding the understanding of the regulatory functions of protein methylation in biological processes.
The researchers developed an isotope-labeling mass spectrometry technique and identified a new type of histidine methylation modifications on C3H1 zinc finger proteins and its methyltransferase, CARNMT1. Molecular simulation results demonstrated that histidine methylation contributes to the stability of zinc finger structures, suggesting that this modification may serve as a general mechanism regulating zinc finger protein activity.
To investigate the biological function of histidine methylation, the researchers focused on CARNMT1’s substrate protein, U2AF1. RNA-seq data in CARNMT1 KO cells and U2AF1 KD cells showed that the loss of histidine methylation affects its pre-RNA splicing function. Furthermore, enhanced cross-linking immunoprecipitation (eCLIP) results for U2AF1 revealed that the absence of methylation impairs U2AF1’s ability to recognize the 3’ splice site, thus causes the alternative splicing.
In summary, this study develops a new method to examine protein methylation and provides fresh insights into how protein methylation regulates cellular processes.
Reference: https://doi.org/10.1038/s41467-024-51979-2
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