Crystal structure of the tRNA‐specific adenosine deaminase from <i>Streptococcus pyogenes</i>

Lee, Wonho; Kim, Young Kwan; Nam, Ki Hyun; Priyadarshi, Amit; Lee, Eun Hye; Kim, Eunice EunKyeong; Jeon, Young Ho; Cheong, Chaejoon; Hwang, Kwang Yeon

doi:10.1002/prot.21456

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…Both monomers cooperate to form a dimer of an overall globular shape presenting the catalytic domain at the dimer interface. As expected, this catalytic domain contains Zn atoms bound to it and a conserved glutamate residue that mediates the proton transfer necessary for the deamination reaction [46,20,47].…”

Section: Structures Of Adatssupporting

confidence: 59%

A‐to‐I editing on tRNAs: Biochemical, biological and evolutionary implications

et al. 2014

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Edited by Wilhelm JustKeywords: Inosine Adenosine deaminase acting on tRNA Transfer RNA Deaminase Codon usage Evolution a b s t r a c t Inosine on transfer RNAs (tRNAs) are post-transcriptionally formed by a deamination mechanism of adenosines at positions 34, 37 and 57 of certain tRNAs. Despite its ubiquitous nature, the biological role of inosine in tRNAs remains poorly understood. Recent developments in the study of nucleotide modifications are beginning to indicate that the dynamics of such modifications are used in the control of specific genetic programs. Likewise, the essentiality of inosine-modified tRNAs in genome evolution and animal biology is becoming apparent. Here we review our current understanding on the role of inosine in tRNAs, the enzymes that catalyze the modification and the evolutionary link between such enzymes and other deaminases. Ó 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Inosine and inosine modification enzymesInosine is a non-canonical nucleoside found in all domains of life. Chemically, it is a guanosine analogue and it only differs from the latter by the lack of the N2 amino group. Inosine is rarely present in DNA but is often observed in different types of RNAs including double-stranded RNAs, tRNAs and viral RNAs [76,63,30]. In RNA, inosine is produced by the deamination of adenosine [31,5]. Generally, 2 groups of RNA adenosine deaminases exist: adenosine deaminases acting on messenger RNAs (ADARs) and adenosine deaminases acting on tRNAs (ADATs), the enzymes of each group being specific for specific modification sites [5,76,24,25].ADARs are present only in metazoans and, in vertebrates, three genes that encode for different ADAR proteins have been described. ADAR1 and ADAR2 are expressed in most tissues and their deamination activity has been confirmed. ADAR3 on the contrary is only expressed in the central nervous system and its function is currently unknown, as it lacks deamination activity [45]. As mentioned, ADARs deaminate adenosines in mRNAs to inosine. Since inosine (which is derived from adenosines), resembles guanosine, A-to-I editing on mRNAs can result in amino acid substitutions during translation, and alterations of splice sites during mRNA processing [76]. Additionally, ADARs can edit non-coding RNAs and have regulatory functions, for example, by affecting the biogenesis, processing and target selection of siRNAs and miRNAs [76].Inosine is found in tRNAs in all domains of life. It is present mainly at three positions on tRNAs: position 34, which is the first nucleotide of the anticodon (wobble-position), position 37 (following the anticodon), and position 57 (at the TWC-loop) (Fig. 1A). Interestingly, at position 34, inosine is the final modified base, while at positions 37 and 57 inosine is found in a methylated state (m 1 I37, m 1 I57 or m 1 Im57) [40,55]. Methyl-inosine 37 has only been found in eukaryotic tRNA Ala [30,40] and the modification involves two enzymatic reactions. First, A37 is deaminated to I3...

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Section: Structures Of Adatssupporting

confidence: 59%

A‐to‐I editing on tRNAs: Biochemical, biological and evolutionary implications

et al. 2014

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“…Based on the crystal structure of S. aureus TadA in complex with a tRNA-like substrate, bases C35 and G37 of tRNA Arg ACG are splayed outward upon binding to TadA and the relatively solvent-exposed base C35 only forms a single hydrogen bond to TadA (14), potentially representing a region more accessible to TadA:tRNA co-evolution. Furthermore, S. pyogenes TadA harbours a C-terminal extension absent from E. coli and S. aureus TadA (68), which might play an additional role in tRNA binding or positioning, thereby contributing to the recognition of the expanded set of tRNA substrates.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of diversified A-to-I editing inStreptococcus pyogenesis governed by changes in mRNA stability

Wulff,

Hahnke,

Lécrivain

et al. 2023

Preprint

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Adenosine-to-inosine (A-to-I) RNA editing plays an important role in the post-transcriptional regulation of eukaryotic cell physiology. However, our understanding of the occurrence, function and regulation of A-to-I editing in bacteria remains limited. Bacterial mRNA editing is catalysed by the deaminase TadA, which was originally described to modify a single tRNA inE. coli. Intriguingly, several bacterial species appear to perform A-to-I editing on more than one tRNA. Here, we provide evidence that in the human pathogenStreptococcus pyogenes, tRNA editing has expanded to an additional tRNA substrate. Using RNA sequencing, we identified more than 27 editing sites in the transcriptome ofS. pyogenesSF370 and demonstrate that the adaptation ofS. pyogenesTadA to a second tRNA substrate has also diversified the sequence context and recoding scope of mRNA editing. Based on the observation that editing is dynamically regulated in response to several infection-relevant stimuli, such as oxidative stress, we further investigated the underlying determinants of editing dynamics and identified mRNA stability as a key modulator of A-to-I editing. Overall, our findings reveal the presence and diversification of A-to-I editing inS. pyogenesand provide novel insights into the plasticity of the editome and its regulation in bacteria.

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“…Since the determination of the first TadA crystal structure in 2005, i.e., TadA from Aquifex aeolicus (AaTadA, PDB 1WWR) [14], TadA structures from multiple bacterial organisms have been solved (PDBs 1WWR, 1Z3A, 2A8N, 2NX8, and 3OCQ) [14][15][16][17]. AaTadA displays an α/β/α three-layered fold and forms a homodimer.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the yeast heterodimeric ADAT2/3 deaminase

et al. 2020

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Background The adenosine-to-inosine (A-to-I) editing in anticodons of tRNAs is critical for wobble base-pairing during translation. This modification is produced via deamination on A34 and catalyzed by the adenosine deaminase acting on tRNA (ADAT) enzyme. Eukaryotic ADATs are heterodimers composed of the catalytic subunit ADAT2 and the structural subunit ADAT3, but their molecular assemblies and catalytic mechanisms are largely unclear. Results Here, we report a 2.8-Å crystal structure of Saccharomyces cerevisiae ADAT2/3 (ScADAT2/3), revealing its heterodimeric assembly and substrate recognition mechanism. While each subunit clearly contains a domain resembling their prokaryotic homolog TadA, suggesting an evolutionary gene duplication event, they also display accessory domains for additional structural or functional purposes. The N-lobe of ScADAT3 exhibits a positively charged region with a potential role in the recognition and binding of tRNA, supported by our biochemical analysis. Interestingly, ScADAT3 employs its C-terminus to block tRNA’s entry into its pseudo-active site and thus inactivates itself for deamination despite the preservation of a zinc-binding site, a mechanism possibly shared only among yeasts. Conclusions Combining the structural with biochemical, bioinformatic, and in vivo functional studies, we propose a stepwise model for the pathway of deamination by ADAT2/3. Our work provides insight into the molecular mechanism of the A-to-I editing by the eukaryotic ADAT heterodimer, especially the role of ADAT3 in catalysis.

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Crystal structure of the tRNA‐specific adenosine deaminase from Streptococcus pyogenes

Cited by 8 publications

References 20 publications

A‐to‐I editing on tRNAs: Biochemical, biological and evolutionary implications

A‐to‐I editing on tRNAs: Biochemical, biological and evolutionary implications

Dynamics of diversified A-to-I editing inStreptococcus pyogenesis governed by changes in mRNA stability

Crystal structure of the yeast heterodimeric ADAT2/3 deaminase

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