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Division of labor in epitranscriptomics: What have we learnt from the structures of eukaryotic and viral multimeric RNA methyltransferases?

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Abstract The translation of an mRNA template into the corresponding protein is a highly complex and regulated choreography performed by ribosomes, tRNAs, and translation factors. Most RNAs involved in this process are decorated by multiple chemical modifications (known as epitranscriptomic marks) contributing to the efficiency, the fidelity, and the regulation of the mRNA translation process. Many of these epitranscriptomic marks are written by holoenzymes made of a catalytic subunit associated with an activating subunit. These holoenzymes play critical roles in cell development. Indeed, several mutations being identified in the genes encoding for those proteins are linked to human pathologies such as cancers and intellectual disorders for instance. This review describes the structural and functional properties of RNA methyltransferase holoenzymes, which when mutated often result in brain development pathologies. It illustrates how structurally different activating subunits contribute to the catalytic activity of these holoenzymes through common mechanistic trends that most likely apply to other classes of holoenzymes. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Processing > Capping and 5′ End Modifications
The class I S‐adenosyl‐l‐methionine (SAM)‐dependent methyltransferase (MTase) fold. (a) Ribbon representation of this fold colored from its N‐terminus (blue) to its C‐terminus (red). The SAM molecule is shown as gray sticks with the methyl group to be transferred highlighted by a purple sphere. The Cα atoms of the three glycine residues from Motif I are shown as blue spheres. The side chains from the two conserved acidic residues interacting with the SAM cofactor are shown as sticks. This figure was generated using the coordinates of the crystal structure of human METTL5 (van Tran et al., 2019). With the exception of Figure 4(d), all figures representing three dimensional structures of protein complexes have been generated using the PYMOL® software version Schrödinger, LLC (http://www.pymol.org/). (b) Topology diagram of the class I SAM‐dependent MTase fold. Helices and strands are colored in light blue and light orange, respectively. Regions where insertions have been observed in various structures of MTase domains adopting this fold are colored in gray. The three glycine residues from motif I are highlighted as black spheres. The methyl group to be transferred onto the substrate is depicted as a purple sphere. The two acidic residues important for SAM binding are shown as red sticks
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TRMT112, a master modifier of translation actors. (a) Representation of the cryo‐EM structure of the mature human 40S with nucleotides modified by the BUD23‐TRMT112 and METTL5‐TRMT112 complexes, highlighted as magenta and orange spheres, respectively. The 18S rRNA is shown in light brown while ribosomal proteins are in gray. The h44 helix, a structural hallmark of the small ribosomal subunit, is colored in black. The mRNA codons present in the A‐, P‐ and E‐sites are colored in red, cyan and green, respectively. (b) The Saccharomyces cerevisiae Bud23‐Trm112 complex bound to SAM (black sticks). The zinc atom bound to yeast Trm112 is shown as a magenta sphere. For the sake of clarity, the same orientation is used in all panels of this figure. TRMT112 elements are labeled in italics in all panels. (c) The human METTL5‐TRMT112 complex bound to SAM (black sticks). (d) The Archaeoglobus fulgidus Trm11‐Trm112 complex bound to SAM (black sticks). The zinc atom bound to A. fulgidus Trm112 is shown as a magenta sphere. The Trm11 THUMP domain is colored pink. (e) The Trm9‐Trm112 complex from the yeast Yarrowia lipolytica. The zinc atom bound to Trm112 is shown as a magenta sphere. (f) The human HEMK2‐TRMT112 complex bound to SAH (black sticks) and to a peptide from its histone H4 substrate (magenta, which methylated Lys12 is shown as sticks). Inset: Chemical structure of N5‐methyl‐glutamine (me‐Gln)
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The tRNA methyltransferase subunits activated by WD‐40 proteins. (a) The Saccharomyces cerevisiae Trm8‐Trm82 m7G46 tRNA MTase bound to SAM. (b) The S. cerevisiae Trm7‐Trm734 Nm34 tRNA MTase. The three WD‐40 domains from Trm734 are shown in different colors
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The TRMT61A‐TRMT6 m1A58 tRNA methyltransferase. (a) The human TRMT61A‐TRMT6 heterodimeric complex. The TRMT6 MTase domain is colored pink. The β‐barrels from TRMT61A and TRMT6 are colored in light blue and purple, respectively. The α‐helical domain from TRMT6 is shown in wine red. (b) Representation of the human TRMT61A‐TRMT6 heterotetrameric complex. The same color as for panel A is used for one heterodimer. For the second one, the TRMT61A and TRMT6 proteins are colored light green and yellow, respectively. (c) Surface representation of the human TRMT61A‐TRMT6 heterotetrameric complex bound to one tRNA substrate (blue), showing that the tRNA binding site is spanning over a large area contributed by subunits from both heterodimers. The same color code as for panel B is used. The A58 tRNA position is shown as an orange sphere. (d) Electrostatic representation of the human TRMT61A‐TRMT6 heterotetrameric complex bound to a tRNA substrate (yellow). The A58 tRNA position is highlighted in green. This panel was generated using the CHIMERA software (Pettersen et al., 2004). Positively charged (10 kBT/e) and negatively charged (−10 kBT/e‐) regions are colored in blue and red, respectively. The orientation is the same as in panel C
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Structure and location of the tRNA modifications discussed in this review. (a) Clover‐leaf representation of a tRNA with the location and the chemical structures (insets) of discussed modifications. The variable loop is shown as a dotted line. Note that the N1‐methylation of adenine and N7‐methylation of guanine rings introduce a positive charge (red sign) on those rings. The Hoogsteen base pair formed between m1A58 and T54 is shown as a dashed line
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The cap and m6A mRNA methyltransferases (MTases). (a) Schematic representation of a eukaryotic mRNA showing the locations of the mRNA marks discussed in this review. Insets: Chemical structures of the 5′ cap and m6A modifications. Note that the N7‐methylation of guanine ring introduces a positive charge (red sign) on the ring. (b) Complex formed between the MTase domains from human METTL3 and METTL14 (orange) proteins. In all figure panels, the active MTase domain is shown in light brown, strands β3 and β6 from the MTase domain are colored in red and blue, respectively. The activating subunits are labeled in italics. The S‐adenosyl‐l‐methionine (SAM) or S‐adenosyl‐homocysteine (SAH) cofactors are shown as black sticks. The methyl group to be transferred from SAM to the product is highlighted by a purple sphere. Labels related to activating subunits are in italics. (c) The RNA guanine‐7 MTase (RNMT) m7G cap MTase bound to the RNMT‐activating miniprotein (RAM, green). The RMNT lobe domain is in light blue. (d) The m7G cap MTase D1‐D12 complex from Vaccinia virus. The D12 subunit is shown in yellow. This figure was generated using the 2VDW PDB code. (e) The SARS‐Cov 2′OH cap MTase complex formed by nsp16 and nsp10 (green) subunits. The zinc atoms bound to nsp10 are shown as magenta spheres. This figure was generated using the 3R24 PDB code
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