Structural insights into the mechanism of human methyltransferase hPRMT4

Abstract

Human PRMT4, also known as CARM1, is a type I arginine methyltransferase protein that catalyse the formation of asymmetrical dimethyl arginine product. Structural studies done to date on PRMT4 have shown that the N-terminal region, Rossmann fold and dimerization arm play an important role in PRMT4 activity. Elucidating the functions of these regions in catalysis remains to be explored. Studies have shown the existence of communication pathways in PRMT4, which need further elucidation. The molecular dynamics (MD) simulations performed in this study show differences in different monomeric and dimeric forms of hPRMT4, revealing the role of the N-terminal region, Rossmann fold and dimerization arm. The study shows the conformational changes that occur during dimerization and SAM binding. Our cross-correlation analysis showed a correlation between these regions. Further, we performed PSN and network analysis to establish the existence of communication networks and an allosteric pathway. This study shows the use of MD simulations and network analysis to explore the aspects of PRMT4 dimerization, SAM binding and demonstrates the existence of an allosteric network. These findings shed novel insights into the conformational changes associated with hPRMT4, the mechanism of its dimerization, SAM binding and clues for better inhibitor designs.

Communicated by Ramaswamy H. Sarma

Keywords:

• PRMT
• arginine methylation
• PRMT4
• allostery
• MD simulation

Disclosure statement

No potential conflict of interest was reported by the authors.