Structural insight into arginine methylation by the mouse protein arginine methyltransferase 7: a zinc finger freezes the mimic of the dimeric state into a single active site

Abstract

Protein arginine methyltransferase 7 (PRMT7) is a type III arginine methyltransferase which has been implicated in several biological processes such as transcriptional regulation, DNA damage repair, RNA splicing, cell differentiation and metastasis. PRMT7 is a unique but less characterized member of the family of PRMTs. The crystal structure of full-length PRMT7 from Mus musculus refined at 1.7 Å resolution is described. The PRMT7 structure is composed of two catalytic modules in tandem forming a pseudo-dimer and contains only one AdoHcy molecule bound to the N-terminal module. The high-resolution crystal structure presented here revealed several structural features showing that the second active site is frozen in an inactive state by a conserved zinc finger located at the junction between the two PRMT modules and by the collapse of two degenerated AdoMet-binding loops.

A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

“…S1) as well as previous small-angle X-ray scattering studies (13) showed that TbPRMT7 forms a homodimer in solution. The juxtaposition of the two tandem PRMT cores in mouse and roundworm PRMT7 crystal structures recapitulates the dimeric TbPRMT7 architecture, sharing a similar overall quaternary structure (19,20). Although only one PRMT module is catalytically active in mouse PRMT7 (MmPRMT7) and roundworm PRMT7 (CePRMT7) (19,20), our data (Table 1), as well as those of others, suggest that dimerization of PRMT7 cores-either by a noncovalent assembly or by juxtaposition of two units as part of one polypeptide-is a prerequisite for catalytic activity (19,20).…”

“…Notably, TbPRMT7 and mammalian PRMT7 have a distinct structural organization (9,10,13,20). Although the mammalian enzymes contain two PRMT cores in tandem, the trypanosomal enzyme contains only one PRMT core.…”

“…Another common feature of PRMTs is the dimerization of the catalytic core that is realized in most cases by noncovalent association of two protomers. Covalent linkage of two PRMT modules has also been observed (19)(20)(21)(22). Although representative structures of type I, II, and III enzymes have been determined (13,19,20,(23)(24)(25), our understanding of product specificity in these enzymes remains fragmentary.…”

“…Covalent linkage of two PRMT modules has also been observed (19)(20)(21)(22). Although representative structures of type I, II, and III enzymes have been determined (13,19,20,(23)(24)(25), our understanding of product specificity in these enzymes remains fragmentary. To unravel the molecular basis of the strict MMA activity of PRMT7 enzymes, we determined the X-ray crystal structure of Trypanosoma brucei PRMT7 (TbPRMT7), which was recently reported in two different crystal forms (13).…”

Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1

“…Although the different PRMTs vary significantly in overall size and sequence, they share a common active site architecture defined by specific amino acids (belonging to the so-called motifs I to IV) known to be key for catalysis (Fig. 1A) (1)(2)(3)(4)12). Most notable in this regard are residues involved in hydrogen bonding to the adenosine moiety of AdoMet and two conserved glutamate residues that form the so-called "double-E loop" critical for chelating and orienting the guanidine group of the target arginine residue.…”