Protein arginine methyltransferase 7 has a novel homodimer‐like structure formed by tandem repeats

Abstract

Edited by Stuart Ferguson Keywords:Protein arginine methyltransferase S-adenosyl-L-homocysteine X-ray crystallography a b s t r a c t Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-L-methionine to nitrogen atoms on arginine residues. Here, we describe the crystal structure of Caenorhabditis elegans PRMT7 in complex with its reaction product S-adenosyl-L-homocysteine. The structural data indicated that PRMT7 harbors two tandem repeated PRMT core domains that form a novel homodimer-like structure. S-adenosyl-L-homocysteine bound to the N-terminal catalytic site only; the C-terminal catalytic site is occupied by a loop that inhibits cofactor binding. Mutagenesis demonstrated that only the N-terminal catalytic site of PRMT7 is responsible for cofactor binding.

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).…”

“…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).…”

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

“…In another example, mammalian PRMT7 and PRMT9 both harbor two catalytic modules in tandem, forming a pseudodimer. The data suggest that in both cases only the N-terminal PRMT module contains conserved residues and binds AdoMet, although the inactive module is necessary for the enzyme activity (52)(53)(54)(55), which is somewhat reminiscent of activation of TbPRMT1 ENZ by TbPRMT1…”

Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2

“…Other PRMTs contain only one methyltransferase domain, which makes this an unusual feature of these two "outlier" PRMTs. Crystallographic studies elucidating the structure of Mus musculus and Caenorhabditis elegans PRMT7 show that AdoMet only binds to the N-terminal domain, and the other methyltransferase domain at the C terminus may have a pseudodimer function (15,16), mimicking the homodimer structure required for activity of other PRMTs upon binding their substrate (PRMT1, PRMT3, and PRMT5, and Trypanosoma brucei PRMT7) (15,(17)(18)(19). Deletion of either domain in PRMT7 abolishes its activity (20), as do amino acid substitutions in the C-terminal domain (8), consistent with a role in forming pseudodimers that are necessary for correct substrate binding.…”