Molecular basis for METTL9-mediated N1-histidine methylation
Xiaoyang Wang, Huabin Xie, Qiong Guo, Dan Cao, Wenwen Ru, Shidong Zhao, Zhongliang Zhu, Jiahai Zhang, Wen Pan, Xuebiao Yao, Chao Xu
Abstract
Methylation is one of the most abundant and common posttranslational modifications (PTMs) and plays important roles in a wide range of cellular events 1 , 2 . Histidine methylation occurs at the N1 or N3 position of the imidazole ring and accounts for ~13% of protein methylation events 3 . Although methylhistidine was found in actin and myosin decades ago 4 , very few mammalian histidine-specific methyltransferases were identified until recently, and several groups identified SETD3 and METTL18 as actin and RPL3 histidine-N3 methyltransferases, respectively 5 , 6 , 7 , 8 , and METTL9 as a histidine-N1 methyltransferase 9 , 10 . Unlike SETD3 or METTL18, which methylates a unique substrate, METTL9 specifically recognizes an xHxH motif (H is for histidine and x denotes small residues.) and catalyzes the methylation of the second histidine. xHxH, as a known metal binding motif, is found in a wide range of metal binding proteins, suggesting the potential role of METTL9-dependent histidine methylation in mediating the metal binding capacities for those proteins. Despite its important role, the molecular mechanism underlying substrate recognition and methylation by METTL9 is largely unknown.