RNA methyltransferases involved in 5' cap biosynthesis

Byszewska, Magdalena; Smietanski, Miroslaw; Purta, Elzbieta; Bujnicki, Janusz M

Some small RNAs, including mammalian U6 and 7SK, mouse B2, and plant U3, present a completely different 5 0 cap structure, which is chemically minimalistic compared to the elaborate guanosine cap. This alternative cap is generated by methylation of a g-phosphate oxygen at the unprocessed 5 0 end of the primary transcript. 17 It is clear that apart from guanosine addition to the 5 0 end, essentially all cap modifications are due to methylations. The cap structure of mRNAs in trypanosomes, m 7 Gpppm 6,6 Am-pAmpCmpm 3 Um, is formed with as many as 8 methylation steps. In all cases that have been experimentally characterized to date, methylations of caps in all organisms and viruses are catalyzed by S-adenosyl-L-methionine (SAM)-dependent methyltransferases ( Table 1) . For the most common types of methylation reactions implicated in cap modification, the crystal structures of the representative proteins have been determined ( Table 2) . All cap methyltransferases characterized structurally belong to the Rossmann Fold Methyltransferase (RFM) superfamily. 18 The topology of the RFM fold is very similar to the typical Rossmann fold (#6-#5-#4-#1-#2-#3), with an additional, 7 th ß-strand inserted into the sheet in an antiparallel manner (#6-"7-#5-#4-#1-#2-#3) (Fig. 1) . 18, 19 The methyl group donor (SAM) binding site is formed by loops following strands 1, 2, and 3, while the substrate to be methylated is typically bound by loops following strands 4, 5, and 6. Various families of RFM enzymes exhibit fusions with other domains, extensions of termini, and insertions within the conserved RFM domain, in particular following strand 5. These elaborations of the common fold are often involved in substrate binding or in oligomerization. 20, 21 In this review, we discuss cellular and viral methyltransferases involved in 5 0 cap RNA biosynthesis, with emphasis on the sequence structure relationships in the light of the experimentally determined structures of enzymes complexed with their ligands. We focus on comparison of enzymes with similar activities that generate products with chemically similar structures.