Phosphorylation at the N-Terminal in Hmt1 Enhances Dimerization by Exposing the Binding Surface

Arginine methylation is a pivotal post-translational modification (PTM) that affects numerous cellular processes, including histone modification, transcriptional regulation, and nuclear import/export. Protein arginine methyltransferases (PRMTs) catalyze these modifications in an <i>S</i>-adenosyl-l-methionine-dependent manner, and their enzymatic activity requires PRMT homodimer formation. Aberrant regulation of PRMT dimerization can impair PRMT function and contribute to diseases development. Hmt1, a primary PRMT in budding yeast, plays a critical role in chromatin remodeling, cell cycle regulation, and PTM-dependent protein activation. A previous study identified phosphorylation of the N-terminal region of the Hmt1 monomer as an essential factor for dimerization. However, the mechanism underlying phosphorylation-dependent dimerization remains unclear. In this study, molecular dynamics (MD) simulations of the Hmt1 monomer were conducted by considering its phosphorylation to examine the conformation of its N-terminal region and clarify how phosphorylation affects dimerization. The MD simulations revealed that phosphorylation reduces the interaction between the N-terminal region and the arm structure, which is essential for forming the Hmt1 homodimer, resulting in greater exposure of the homodimer's binding surface. This conformational change is driven by the negative charge and hydrophilicity of the phosphate group and by secondary structure formation that decreases flexibility of the N-terminal region.