Towards the structural characterization of the human methyltransferome

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Highlights

  • •

    Methyltransferases (MTases) are structurally aligned and classified.

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    Structures of the human methyltransferome are tabulated.

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    New complexes show histone readers and epigenetic mechanisms of MTase activation.

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    MTase-activator complexes show mechanisms of MTase activation beyond chromatin.

Approximately 2000 structures of methyltransferases (MTases) are currently available, displaying fifteen different folds for binding a methyl donor and providing molecular level insight into nearly half the human methyltransferome. Several MTases involved in gene expression and regulation are catalytically inefficient when isolated, and their catalytic domains often show inhibitory active site architectures. Recently reported structures of complexes that more closely reflect biological context have begun to reveal the structural basis of activation. DNA and particular histone MTases are allosterically activated by binding histone modifications using reader domains or separate reader proteins, and some MTases operating beyond chromatin are activated by binding an activator protein. In this review, we describe the structural status of the human methyltransferome and then discuss newly revealed structural mechanisms of MTase activation.

Section snippets

Structural classification and distribution

The Protein Data Bank (PDB) currently contains about 2000 structures of methyltransferases (MTases), which can be classified according to the structural fold used to bind the methyl donor. Greater than 90% of the more than 300 methylation reactions classified under EC 2.1.1 use S-adenosylmethionine (SAM) as the methyl donor. SAM-dependent methylation reactions can be further subdivided into nucleophilic substitution or radical reactions. Structural alignment and clustering of MTase catalytic

Structural characterization of the human methyltransferome

Structural coordinates for nearly half of the MTases of the putative human methyltransferome [22] are currently available (Figure 2). A total of 201 known or predicted human MTases use eight SAM-dependent and three SAM-independent fold classes. The human 7-β-strand, SET, and SPOUT classes have 125, 56, and 8 members, respectively, of which 51, 57, and 50%, respectively, have human or orthologous eukaryotic structures available for their SAM-binding folds.

Several recently reported human MTase

Epigenetic mechanisms of MTase activation

The DNA MTases DNMT1, DNMT3A, and DNMT3B silence gene transcription by catalyzing cytosine C5 methylation of CpG dinucleotides within, e.g., gene promoters. In the classical model, DNMT3A and DNMT3B are de novo MTases, whereas DNMT1 is a maintenance MTase that acts on the unmethylated strand of hemi-methylated DNA during replication [37].

Structural results show that DNMT1 binds unmethylated DNA between its zinc finger (CXXC) and catalytic domains, but the target base remains unflipped and is

MTase activation beyond chromatin

rRNA and tRNA post-transcriptional modifications provide the chemical diversity needed to form the complex structures of the ribonucleic arm of the protein translation apparatus. Although more than 100 rRNA 2′-O methylations are installed by box C/D small nucleolar ribonucleoproteins [60, 61], other RNA methylations are catalyzed by individual enzymes, a subset of which utilize one or more activator proteins [62].

A series of structural studies has been performed on fungal orthologs of four

Tip of an iceberg of MTase switches

Several of the structures discussed in this review represent milestones in MTase structural biology and have revealed new mechanisms of MTase activation important for gene expression and regulation. However, additional switches for modulating MTase activity have been discovered and a myriad more likely await discovery and structural characterization. Given the involvement of many MTases in gene expression and cancer-related pathways, further characterization of their structures and

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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