Many paths to methyltransfer: a chronicle of convergence

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Abstract

S-adenosyl-l-methionine (AdoMet) dependent methyltransferases (MTases) are involved in biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing. Five different structural folds (I–V) have been described that bind AdoMet and catalyze methyltransfer to diverse substrates, although the great majority of known MTases have the Class I fold. Even within a particular MTase class the amino-acid sequence similarity can be as low as 10%. Thus, the structural and catalytic requirements for methyltransfer from AdoMet appear to be remarkably flexible.

Section snippets

In the beginning, a MTase was a MTase was a MTase

Starting with the M.HhaI DNA-MTase structure in 1993 [4], a continuing string of structures for AdoMet-dependent MTases have been reported. These structures are remarkably similar, comprising a seven-stranded β sheet with a central topological switch-point and a characteristic reversed β hairpin at the carboxyl end of the sheet (6↑ 7↓ 5↑ 4↑ 1↑ 2↑ 3↑; Fig. 1a). This sheet is flanked by α helices to form a doubly wound open αβα sandwich, and is henceforth referred to as the Class I MTase

A lesson in cobalamin

As early as 1996, there was a hint that not all AdoMet-dependent MTases would follow the same structural theme. The Escherichia coli cobalamin (vitamin B12)-dependent methionine synthase, MetH, generates methionine from homocysteine, transferring a methyl group from a folate derivative to the bound cobalamin and thence to homocysteine. Periodically, the B12 cobalt is oxidized to a dead-end form, and reactivation requires reductive methylation using AdoMet, flavodoxin and an additional

Knotty new MTase structures SET to SPOUT

This past year has provided two more disparate MTase structures. The SPOUT family of RNA MTases provides the only known cases of Class IV structure 24, 25, 26. These enzymes are unique in three ways: (1) they include a six-stranded parallel β sheet flanked by seven α helices, of which the first three strands form half of a Rossman fold (Fig. 1d); (2) their active site is located near the subunit interface of a homodimer, and might encompass residues extending from both subunits; and (3) the

Conformations of AdoMet and AdoHcy

The bound AdoMet or AdoHcy ligand exhibits significantly different conformations in the five structural classes, which emphasizes its flexibility. Figure 3a compares the prototypical AdoMet and AdoHcy conformations of each structural class by aligning the molecules via their ribose moieties. The ribose ring of AdoMet in Class I adopts an envelope 2′-endo conformation, with its base in the anti position at ∼135° (defined by the O4′–C1′–N9–C4 dihedral; Fig. 3b). The ribose rings of the other

A diverse set of mechanisms for a conserved class of MTase

Substrate-bound complexes have been determined mainly for Class I structures, although recently a Class V (SET) MTase in complex with a lysine-containing peptide has also been determined [36]. All MTases are thought to proceed with direct transfer of the methyl group to substrate with inversion of symmetry in an SN2-like mechanism 37, 38. This reaction also requires that a proton be removed before, concurrent with, or after methyl transfer. Even within the structurally conserved family of Class

Concluding remarks

Evolution has independently achieved AdoMet-dependent MTase activity at least five times, producing five unique structural MTase classes. Most of the other examples of analogous enzyme families also use substrates, such as ATP or NAD, that include a nucleotide ‘handle’ for binding. The Class I and Class IV MTases are plausibly derived from Rossmann-fold proteins, and even the Class III CbiF structure contains a GxGxG nucleotide-binding motif, but uses it unconventionally. The Class II and Class

Acknowledgments

We thank Osnat Herzberg and Steve Gamblin for early release of coordinates. H.L.S. was supported by grants from NIH (GM56775 and DK02794), R.M.B. was supported by a grant from the U.S. National Science Foundation (MCB-9904523), and X.C. was supported by NIH (GM49245 and GM61355) and the Georgia Research Alliance.

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