Structure of dengue virus: implications for flavivirus organization, maturation, and fusion

Abstract

Protein methylation on arginine and lysine residues is emerging to be an important post-translational modification in eukaryotes. The methylation affects interaction of target protein with other molecules, regulating cellular processes such as RNA processing and/or transport, chromatin structure and gene transcription. Protein arginine (R) methyltransferases (PRMT) have up to 8 members in human. PRMT1 is the predominant PRMT in mammal, accounting for 85% of the cellular PRMT activity and is essential for early postimplantation development in mouse. Here we describe the crystal structures of rat PRMT1 in complex with peptides containing single or three arginines, respectively. The results reveal a two-domain structure -an AdoMet-binding domain and a barrel-like domain -with the active site pocket located in between the two domains. Mutagenesis studies confirmed that two glutamic acids in the active site are essential for enzymatic activity and the dimerization of PRMT is essential for methyl donor AdoMet binding. Three peptide-binding channels are identified. The multiple peptide binding channels are probably important for binding of PRMT1 substrates that often contain multiple arginines in RGG or RXR contexts.