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 Professor Cheng Hong from the Center for Excellence in Molecular Cell Science of Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), in collaboration with Professor Ye Mingliang and Professor Li Guohui from CAS’s Dalian Institute of Chemical Physics, and Professor Wang Zefeng from CAS’s Shanghai Institute of Nutrition and Health, 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 U2AF1 KD cells’ 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.

Histidine methylation contributes to the stability of zinc finger structures, which plays a crucial auxiliary role in U2AF1’s recognition of the 3’ splice site and exon splicing [IMAGE: SIBCB]

For more information, please contact:

Professor Cheng Hong

E-mail: hcheng@@sibcb.ac.cn

Center for Excellence of Molecular Cell Science,

Chinese Academy of Sciences

Professor Ye Mingliang

E-mail: mingliang@dicp.ac.cn

Dalian Institute of Chemical Physics,

Chinese Academy of Sciences

Sources: Center for Excellence of Molecular Cell Science,

and Dalian Institute of Chemical Physics,

Chinese Academy of Sciences