AdoMet-dependent methylation, DNA methyltransferases and base flipping - PubMed (original) (raw)

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AdoMet-dependent methylation, DNA methyltransferases and base flipping

X Cheng et al. Nucleic Acids Res. 2001.

Abstract

Twenty AdoMet-dependent methyltransferases (MTases) have been characterized structurally by X-ray crystallography and NMR. These include seven DNA MTases, five RNA MTases, four protein MTases and four small molecule MTases acting on the carbon, oxygen or nitrogen atoms of their substrates. The MTases share a common core structure of a mixed seven-stranded beta-sheet (6 downward arrow 7 upward arrow 5 downward arrow 4 downward arrow 1 downward arrow 2 downward arrow 3 downward arrow) referred to as an 'AdoMet-dependent MTase fold', with the exception of a protein arginine MTase which contains a compact consensus fold lacking the antiparallel hairpin strands (6 downward arrow 7 upward arrow). The consensus fold is useful to identify hypothetical MTases during structural proteomics efforts on unannotated proteins. The same core structure works for very different classes of MTase including those that act on substrates differing in size from small molecules (catechol or glycine) to macromolecules (DNA, RNA and protein). DNA MTases use a 'base flipping' mechanism to deliver a specific base within a DNA molecule into a typically concave catalytic pocket. Base flipping involves rotation of backbone bonds in double-stranded DNA to expose an out-of-stack nucleotide, which can then be a substrate for an enzyme-catalyzed chemical reaction. The phenomenon is fully established for DNA MTases and for DNA base excision repair enzymes, and is likely to prove general for enzymes that require access to unpaired, mismatched or damaged nucleotides within base-paired regions in DNA and RNA. Several newly discovered MTase families in eukaryotes (DNA 5mC MTases and protein arginine and lysine MTases) offer new challenges in the MTase field.

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Figures

Figure 1

Figure 1

Examples of DNA MTases (see Table 1). M._Hha_I (5mC), M._Hae_III (5mC), human DNMT2, M._Dpn_II (N6mA, α), M._Pvu_II (N4mC, β), M._Rsr_I (N6mA, β) and M._Taq_I (N6mA, γ). The AdoMet-dependent MTase fold is colored in green (β strands), cyan (α helices) and red (the loops after the carboxyl ends of β strands). The region(s) outside the MTase fold is colored in gray.

Figure 2

Figure 2

Examples of RNA MTases. VP39 (mRNA nucleoside-2′-O), ErmC′ or closely related ErmAM (rRNA N6mA), FtsJ and fibrillarin homolog.

Figure 3

Figure 3

Examples of protein MTases. CheR (glutamate-O), PRMT3 (arginine-N), Hmt1 (arginine-N) and PIMT (isoaspartate-O).

Figure 4

Figure 4

Examples of small molecule MTases: COMT (catechol-O), GNMT (glycine-N), and IOMT (isoflavone-O) or closely related ChOMT (chalcone-O).

Figure 5

Figure 5

Examples of DNA base flipping proteins (see Table 3) in complex with oligonucleotide containing an abasic site. (A) M._Hha_I (a DNA 5mC MTase), (B) human UDG, (C) human AAG, (D) E.coli endonuclease IV, (E) E.coli AlkA and (F) human HAP1. The protein is colored gray, the DNA is represented as a magenta stick model with the flipped abasic site in green, usually buried in a surface pocket in the protein.

Figure 6

Figure 6

30S ribosomal subunit flipped-out A1492 and A1493 from helix 44 of 16S RNA by binding of (left) paromomycin (seen in the difference electron density) and (right) initiation factor IF1 (in purple). The protein S12 is in orange, helix H44 in cyan.

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