Crystal structure of tRNA(m1G37)methyltransferase: insights into tRNA recognition

Ahn, Hyung Jun; Kim, Hyeon‐Woo; Yoon, Hye‐Jin; Lee, Byung Ii; Suh, Se Won; Yang, Jong Oh

doi:10.1093/emboj/cdg269

Cited by 129 publications

(223 citation statements)

References 43 publications

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“…The TrmD structure was solved at 2.25 Å resolution with the Haemophilus influenzae enzyme, which shares 83% sequence identity and 91% similarity with E. coli TrmD. As seen in the previous structures of TrmD (Ahn et al 2003;Elkins et al 2003), the two active sites in the dimeric H. influenzae enzyme were symmetrically assembled in the dimer interface, with each consisting of residues from the AdoMet-binding motifs in the N-terminal domain of one monomer and residues from the tRNAbinding motifs in the C-terminal domain of the second monomer. A comparison with the previous AdoMet-bound structure of TrmD (Ahn et al 2003) revealed that the two adenosine molecules bound in the new structure were in virtually overlapping positions as the adenosine moiety of the previous structure (Fig.…”

Section: X-ray Structural Analysis Of Adenosine-bound Trmd and Trm5 Cmentioning

confidence: 90%

“…While different in spatial configuration, each network is elaborate and comprehensive in the stabilization of the N 1 , N 6 , and N 7 of the adenine ring, the 29-and 39-OH of the ribose, and the carboxyl and amino groups of methionine in the methyl donor. These stabilizing forces are well visualized in a binary structure of TrmD with AdoMet and are preserved in a product complex with S-adenosyl homocysteine (AdoHcy) (Ahn et al 2003;Elkins et al 2003). They are also clearly identified in a binary structure of Trm5 with sinefungin and in a ternary structure with AdoMet and tRNA (Goto-Ito et al 2008).…”

Section: Introductionmentioning

confidence: 86%

“…TrmD functions as a homodimer and binds AdoMet using a rare trefoilknot fold (Ahn et al 2003;Elkins et al 2003), whereas Trm5 functions as a monomer and binds AdoMet using the popular protein fold known as the Rossmann fold (Goto-Ito et al 2008. Importantly, crystal structures of these enzymes show that the AdoMet structure when bound to TrmD exists in an L-shaped bent conformation (Ahn et al 2003), where the methionine moiety bends over the adenosine moiety, whereas the AdoMet structure when bound to Trm5 exists in an extended open conformation (Fig. 1;Goto-Ito et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Differentiating analogous tRNA methyltransferases by fragments of the methyl donor

Lahoud¹,

Goto-Ito²,

Yoshida³

et al. 2011

RNA

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Bacterial TrmD and eukaryotic-archaeal Trm5 form a pair of analogous tRNA methyltransferase that catalyze methyl transfer from S-adenosyl methionine (AdoMet) to N 1 of G37, using catalytic motifs that share no sequence or structural homology. Here we show that natural and synthetic analogs of AdoMet are unable to distinguish TrmD from Trm5. Instead, fragments of AdoMet, adenosine and methionine, are selectively inhibitory of TrmD rather than Trm5. Detailed structural information of the two enzymes in complex with adenosine reveals how Trm5 escapes targeting by adopting an altered structure, whereas TrmD is trapped by targeting due to its rigid structure that stably accommodates the fragment. Free energy analysis exposes energetic disparities between the two enzymes in how they approach the binding of AdoMet versus fragments and provides insights into the design of inhibitors selective for TrmD.

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Section: X-ray Structural Analysis Of Adenosine-bound Trmd and Trm5 Cmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differentiating analogous tRNA methyltransferases by fragments of the methyl donor

Lahoud¹,

Goto-Ito²,

Yoshida³

et al. 2011

RNA

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show abstract

“…Eukaryotes and archaea employ the Trm5 enzyme (Bjork et al 2001;Christian et al 2004), whereas bacteria use the TrmD enzyme (Bystrom and Bjork 1982a,b). While both enzymes use AdoMet as the methyl donor to convert G37-tRNA to m 1 G37-tRNA, they are fundamentally distinct in structure (Ahn et al 2003;Christian et al 2004;Goto-Ito et al 2008, 2009, in kinetics (Christian et al 2010b), and in substrate recognition (Christian and Hou 2007;Lahoud et al 2011;Sakaguchi et al 2012). The lack of similarity between TrmD and Trm5 has led to the suggestion that specific targeting of TrmD, without affecting the Homo sapiens Trm5 (HsTrm5), would be a highly attractive strategy in developing the next generation of antibiotics (White and Kell 2004).…”

Section: Introductionmentioning

confidence: 99%

Conservation of structure and mechanism by Trm5 enzymes

Christian

Gamper

Hou

2013

RNA

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Enzymes of the Trm5 family catalyze methyl transfer from S-adenosyl methionine (AdoMet) to the N 1 of G37 to synthesize m 1 G37-tRNA as a critical determinant to prevent ribosome frameshift errors. Trm5 is specific to eukaryotes and archaea, and it is unrelated in evolution from the bacterial counterpart TrmD, which is a leading anti-bacterial target. The successful targeting of TrmD requires detailed information on Trm5 to avoid cross-species inhibition. However, most information on Trm5 is derived from studies of the archaeal enzyme Methanococcus jannaschii (MjTrm5), whereas little information is available for eukaryotic enzymes. Here we use human Trm5 (Homo sapiens; HsTrm5) as an example of eukaryotic enzymes and demonstrate that it has retained key features of catalytic properties of the archaeal MjTrm5, including the involvement of a general base to mediate one proton transfer. We also address the protease sensitivity of the human enzyme upon expression in bacteria. Using the tRNA-bound crystal structure of the archaeal enzyme as a model, we have identified a single substitution in the human enzyme that improves resistance to proteolysis. These results establish conservation in both the catalytic mechanism and overall structure of Trm5 between evolutionarily distant eukaryotic and archaeal species and validate the crystal structure of the archaeal enzyme as a useful model for studies of the human enzyme.

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“…2), it appears that the RNA-modifying enzymes responsible for producing the 5-taurinomethyl and 2-thio groups of the wobble bases of these mt tRNAs belong to a class of enzymes that recognize the whole tertiary structure of the tRNA, 15 such as tRNA m 1 G37 methyltransferase (TrmD). 16 In other words, the positions of these pathogenic point mutations act as determinants for the biosynthesis of τm 5 U and τm 5 s 2 U. We have recently reported the identification and characterization of the tRNA-modifying enzyme MTU1 (mitochondrial tRNA-specific 2-thiouridylase 1) that is responsible for the 2-thiolation of the wobble position in human and yeast mt tRNAs.…”

Section: Post-transcriptional Wobble Modification Deficiency In Mutanmentioning

confidence: 99%

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

Kirino

Suzuki

2005

RNA Biology

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A growing number of mutations in mitochondrial (mt) tRNA genes have been found to associate with human mitochondrial diseases. Our previous analysis of mutant mt tRNAs isolated from cells derived from patients with mitochondrial diseases revealed the lack of a post-transcriptional taurine-modification at the anticodon wobble uridine in two mt tRNAs bearing typical pathogenic mutations: mt tRNA Leu(UUR) with either the MELAS 3243 or 3271 mutation and mt tRNA Lys with the MERRF 8344 mutation. We here summarize our recent studies that clarify the molecular basis of the defective mitochondrial translation caused by this wobble modification deficiency. The MERRF mt tRNA Lys lacking the wobble modification cannot translate either of its codons (AAA and AAG), while the translational activity of MELAS mt tRNA Leu(UUR) lacking wobble modification is more depressed in decoding of UUG codon than UUA codon. These findings suggest that the wobble modification deficiency plays a primary role in the molecular pathogenesis of the MELAS and MERRF mitochondrial diseases.Point mutations as well as large scale deletions in mitochondrial DNA (mtDNA) are associated with a wide spectrum of human diseases arising from mitochondrial dysfunction. 1,2 Over 150 different pathogenic mutations have been reported so far, more than half of which are located within mt tRNA genes. 1,2 The clinical features of mitochondrial diseases often depend on the mt tRNA species and/or the positions of the mutations involved. However, it is not clear how, at the molecular level, the mutant mt tRNAs actually cause mitochondrial dysfunction and specify the clinical features they generate. If a pathogenic mutation in the mt tRNA gene does not affect mtDNA replication or transcription of the corresponding mt tRNA, it can be assumed that its deleterious effect is exerted at the post-transcriptional level. In other words, it may affect mt tRNA maturation, modification, folding, or aminoacylation, its association with translation factors, and/or various functions on the ribosome. To elucidate the essential molecular pathogenesis of mitochondrial diseases, detailed structural and functional analyses of the mutant mt tRNAs are thus required.We have recently found that of the various post-transcriptional events that an mt tRNA mutation could potentially impair, some mutant mt tRNAs fail to undergo particular post-transcriptional modifications. We previously identified two novel taurine-containing modified uridines [5-taurinemethyluridine (τm 5 U) and 5-taurinomethyl2-thiouridine (τm 5 s 2 U)] at the anticodon first (wobble) position of some species of mammalian mt tRNAs (Fig. 1). 3 What is more, these taurine-containing modifications were lacking in the mutant mt tRNAs from two typical mitochondrial diseases. Our additional analyses suggest that the absence of these modifications can be the main cause of the mitochondrial dysfunction associated with these diseases.

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Crystal structure of tRNA(m1G37)methyltransferase: insights into tRNA recognition

Cited by 129 publications

References 43 publications

Differentiating analogous tRNA methyltransferases by fragments of the methyl donor

Differentiating analogous tRNA methyltransferases by fragments of the methyl donor

Conservation of structure and mechanism by Trm5 enzymes

Human Mitochondrial Diseases Associated with tRNA Wobble Modification Deficiency

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