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Structure of Trna-Modifying Enzyme Tias and Motions of Its Substrate Binding Zinc Ribbon

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Structure of Trna-Modifying Enzyme Tias and Motions of Its Substrate Binding Zinc Ribbon Article Structure of tRNA-Modifying Enzyme TiaS and Motions of Its Substrate Binding Zinc Ribbon Jianshu Dong 1,2,3,4,6,10, Fahui Li 6, Feng Gao 6, Jia Wei 6, Yajing Lin 6, Yong Zhang 6, Jizhong Lou 6, Guangfeng Liu 9, Yuhui Dong 8, Lin Liu 7, Hongmin Liu 3, Jiangyun Wang 6 and Weimin Gong 5,6, 1 - School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China 2 - Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou 450001, PR China 3 - Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China 4 - Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou University, Zhengzhou 450001, PR China 5 - Hefei National Laboratory for Physical Science at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China 6 - Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 7 - Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China 8 - Beijing Synchrotron Radiation Facility and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China 9 - Shanghai Synchrotron Radiation Facility and Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201204, China 10 - University of Chinese Academy of Sciences, Beijing 100864, China Correspondence to Jianshu Dong and Weimin Gong: J. Dong is to be contacted at: School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.; W. Gong, is to be contacted at: Hefei National Laboratory for Physical Science at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China. [email protected]; [email protected] https://doi.org/10.1016/j.jmb.2018.08.015 Edited by Yigong Shi Abstract The accurate modification of the tRNAIle anticodon wobble cytosine 34 is critical for AUA decoding in protein synthesis. Archaeal tRNAIle2 cytosine 34 is modified with agmatine in the presence of ATP by TiaS (tRNAIle2 agmatidine synthetase). However, no structure of apo-form full-length TiaS is available currently. Here, the crystal structures of apo TiaS and a complex of TiaS–agmatine–AMPPCP–Mg are presented, with properly folded zinc ribbon and Cys4-zinc coordination identified. Compared with tRNAIle2-bound form, the architecture of apo TiaS shows a totally different conformation of zinc ribbon. Molecular dynamics simulations of the docking complex between free-state TiaS and tRNAIle2 suggest that zinc ribbon domain is capable of performing large-scale motions to sample substrate binding-competent conformation. Principle component analysis and normal mode analysis show consistent results about the relative directionality of functionally correlated zinc ribbon motions. Apo TiaS and TiaS–agmatine–AMPPCP–Mg/TiaS–AMPCPP–Mg complex structures capture two snapshots of the flexible ATP-Mg binding p2loop step-by-step stabilization. Research from this study provides new insight into TiaS functional mechanism and the dynamic feature of zinc ribbons. © 2018 Elsevier Ltd. All rights reserved. Introduction cytosine 34 (Cyt34) is crucial for AUA deciphering in both bacteria and archaea [3–7]. In eukaryotes, the Of the more than 1 hundred currently known naturally modified 34th-base pseudouridine or inosine is occurring post-transcriptional modifications, tRNA responsible for recognition of the third-base adenine contains the greatest chemical diversity [1,2].The of the AUA codon [8,9]. For most bacteria [10],Tils modification of tRNAIle2 anticodon wobble position (tRNAIle2 lysidine synthetase) modifies tRNAIle2 with 0022-2836/© 2018 Elsevier Ltd. All rights reserved. J Mol Biol (2018) 430, 4183–4194 4184 tRNA-Modifying Enzyme TiaS lysine, thus changing both the tRNA identity and significant effects on the agmatine modification activity, specificity for codon recognition [4,11–18]. Without but mutation with the acceptor stem of tRNAIle2 lysine modification, precursor of tRNAIle is charged substituted by that of tRNAMet abolishes the activity. with methionine rather than isoleucine. Recently, AUA While the deletion of ZRD seems to have little impact on decoding system is uncovered in some Archaea phyla, ATP hydrolysis activity, tRNAIle2 phosphorylation and namely, Euryoarchaeota, Crenarchaeota and Thau- agmatination activities are sharply reduced. Also, point marchaeota [19–21]. Agmatine, a polyamine also mutations of residues at TiaS ZRD (R369A, or C352A– found in the mammalian nervous system [22,23],is C355A double mutation) severely impair agmatine utilized to modify tRNAIle2 Cyt34, by joining the amino incorporation activity. However, another ZRD point group of agmatine with the 2′ carbon of the pyrimidine mutation, E360A, unexpectedly increases agmatidine ring; the resulted new nucleotide agmatidine or agm2C yield. is found in Haloarcula marismortui, Methanococcus Previously, crystal structures of TiaS at three different maripaludis, Sulfolobus solfataricus, Sulfolobus states have been successfully solved (TiaS–tRNAIle2– tokodaii, Archaeoglobus fulgidus and some other ATP, TiaS–tRNAIle2–AMPCPP–agmatine and TiaS archaea [19–21]. After modification, the third tertiary lacking ZRD with agmatine), which suggest the amine group of the pyrimidine ring is protonated to form molecular basis of agm2C formation [25]. However, secondary amine group and can then donate instead of the fourth domain of TiaS essential for substrate tRNA accept proton in hydrogen bonding. The amine group at selection is still largely uncharacterized, and no C4 position is converted to imino group. The modified structural information of apo full-length TiaS enzyme tRNAIle2 could then decode AUA rather than AUG is available so far. Previously, we have reported full- codon via agmatidine34–adenosine unorthodox base length TiaS enzyme structure without substrate tRNA pairing [19–21,24]. As a consequence, the mature but with AMPPCP and click-reactive compound N-(4- tRNAIle is isoleucylated, while the unmodified tRNAIle aminobutyl)-2-azidoacetamide (AGN) bound at the precursor is methionylated [19], which highlights the agmatine binding pocket, revealing the structural significance of the modification. The enzyme catalyzing basis of site- and sequence-specific covalent labeling this modification is named tRNAIle2 agmatidine synthe- of RNAs in mammalian cells (4RVZ.pdb) [29],butZRD tase (TiaS). and the functional significance have not been dis- Catalytic mechanism of tRNAIle2 agmatidine syn- cussed. Here, the crystal structures of apo full-length thesis is uncovered recently through structural and TiaS with intact fourth domain at 2.5-Å resolution and a biochemical studies of TiaS–tRNAIle2 complex complex of TiaS–agmatine–AMPPCP–Mg without [25–28]. TiaS is found to be able to modify tRNAIle2 tRNA are presented, with Cys4-zinc coordination and with the presence of agmatine and ATP without fourth domain zinc ribbon identified. Zinc ribbon/finger adenylated intermediate. TiaS is a four-domain motifs are prevalent in various protein families, which protein; the N-terminal domain responsible for ATP play key roles in a variety of life processes [30–38], binding is named Thr18–Cyt34 kinase domain mediating protein–protein, protein–DNA or protein– (TCKD), as TiaS is able to phosphorylate both its RNA interactions. Various kinds of residue combina- own conservative Thr18 and the tRNAIle2 Cyt34 for tions (C2H2, C4 or C2HC, etc.) are employed to chelate activation. The second and third domains are named zinc atom [38–40], with C2H2 zinc finger regarded as ferredoxin-like fold (FLD) and OB fold (OBD), respec- the classical. ZRD recognizes the acceptor arm of tively. Extensive site-directed mutagenesis study tRNAIle2 in a base-specific manner [25].HereTiaS also supports the functional assignment of the enzyme crystal structures present different conforma- first three domains as the enzyme catalytic core tions from tRNA-bound state. The functionally correlat- [21,25,26]. The anticodon loop of tRNAIle2 binds to ed direction preferences of zinc ribbon motions upon the inter-domain cavity of the TiaS enzyme core. TiaS– substrate binding uncovered from molecular dynamics tRNAIle2–ATP and TiaS–tRNAIle2–AMPCPP– and normal mode analysis (NMA) reveal an amazing agmatine complex structures show similar conforma- new attribute of zinc ribbons, providing fresh insight into tion of TiaS enzyme. tRNAIle2 recognition and modification mechanism. The The C terminus of TiaS, which is responsible for implications for applied research on targetable protein tRNAIle2 acceptor arm recognition and substrate engineering are discussed as well. selection, is named zinc ribbon domain (ZRD) domain – for its similarity to the zinc ribbon-like fold [25,26].TiaS Results tRNAIle2 structures show that ZRD interacts with the major groove of the tRNAIle2 acceptor arm. Because of the presence of two other kinds of tRNA (the initiator Archaeal TiaS structure and its zinc ribbon and elongator tRNAsMet) in the cell that bear the same anticodon loop sequence, TiaS should discriminate The crystal structure of free full-length archaeal tRNAIle2 precursor from other tRNAs like tRNAMet by AfTiaS was determined at 2.5-Å resolution (Fig. 1, recognizing acceptor stem regions [25].Replacingthe Table 1). X-ray fluorescence analysis suggested the anticodonstemoftRNAIle2 with that of tRNAMet has no presence of zinc element in TiaS enzyme crystals.
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