Structure and Function of Protein Arginine Methyltransferase PRMT7

Abstract

PRMT7 is a member of the protein arginine methyltransferase (PRMT) family, which methylates a diverse set of substrates. Arginine methylation as a posttranslational modification regulates protein-protein and protein-nucleic acid interactions, and as such, has been implicated in various biological functions. PRMT7 is a unique, evolutionarily conserved PRMT family member that catalyzes the mono-methylation of arginine. The structural features, functional aspects, and compounds that inhibit PRMT7 are discussed here. Several studies have identified physiological substrates of PRMT7 and investigated the substrate methylation outcomes which link PRMT7 activity to the stress response and RNA biology. PRMT7-driven substrate methylation further leads to the biological outcomes of gene expression regulation, cell stemness, stress response, and cancer-associated phenotypes such as cell migration. Furthermore, organismal level phenotypes of PRMT7 deficiency have uncovered roles in muscle cell physiology, B cell biology, immunity, and brain function. This rapidly growing information on PRMT7 function indicates the critical nature of context-dependent functions of PRMT7 and necessitates further investigation of the PRMT7 interaction partners and factors that control PRMT7 expression and levels. Thus, PRMT7 is an important cellular regulator of arginine methylation in health and disease.

Keywords: PRMT7; cancer; epigenetics; immunity; pluripotency; protein arginine methylation.

Figure 1

General overview of protein arginine methylation modes (left) and PRMT family domain structure (right).

Figure 2

Evolutionary analysis of known PRMT7 proteins. Known PRMT7 sequences from the UniProt database were aligned, and cladogram-rendered using ClustalW2 and simple phylogeny software (EBI).

Figure 3

Crystal structure of MmPRMT7 in the complex with SAH (PDB ID: 4C4A). (A) Overall structure of MmPRMT7 is shown in the surface representation color-coded according to its domain boundaries. The two catalytic modules (N and C) in MmPRMT7 are divided by a dashed line. (B) Module-N of MmPRMT7 is shown as cartoon representation in green (SAM-binding domain), orange (β-barrel domain) and blue (dimerization arm), and SAH in yellow sticks.

Figure 4

PRMT7 SAM-binding pocket comparison and occupancy by the inhibitory compound SGC 8158. (A) Comparison of SAM-binding domains of modules N and C. Overlay of module-N (in green) and module-C (in grey) SAM-binding domains of MmPRMT7 in complex with SAH (yellow). (B) Close-up view of module-N SAM-binding domain in complex with SGC8158 chemical probe (cyan) (PDB ID: 6OGN). The SAM-binding domains for both MmPRMT7-SGC8158 and TbPRMT7-SAH in complex with H4 peptide (PDB ID: 4M38) were superimposed to show the SGC8158 binding mode relative to SAH (yellow) and H4 peptide (magenta).