Structural model of the M7G46 Methyltransferase TrmB in complex with tRNA

Blersch, Katharina F.; Burchert, Jan-Philipp; August, Sophie-Charlotte; Welp, Luisa M.; Neumann, Piotr; Köster, Sarah; Urlaub, Henning; Ficner, Ralf

doi:10.1080/15476286.2021.1925477

Cited by 10 publications

(11 citation statements)

References 49 publications

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“…Interestingly, E. coli TrmB binds tRNA with a lower affinity compared to its characterized homolog. Homodimeric B. subtilis TrmB was shown to bind tRNA Phe in the absence of SAM with an affinity of about 0.1 µM using fluorescence anisotropy (25). This raises the possibility that TrmB enzymes with different quaternary structures may have distinct tRNA binding mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, we prepared two inactive TrmB variants that we hypothesized would retain tRNA binding ability while being unable to methylate tRNA: TrmB D144A and T217A (Figure 1B). Both residues are proposed to participate in methylation, wherein the side chain of the aspartate equivalent to D144 has been shown to form hydrogen bonds with N6 of the SAM adenosine moiety in B. subtilis TrmB (25). Residue T217 is present within the TrmB-specific insertion that is unstructured in E. coli TrmB (8).…”

Section: Trmb Variant Binding To Trna Phementioning

confidence: 99%

“…TrmB was shown to bind tRNA Phe in the absence of SAM with an affinity of about 0.1 µM using fluorescence anisotropy(25). This raises the possibility that TrmB enzymes with different quaternary structures may have distinct tRNA binding mechanisms.…”

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confidence: 99%

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Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB

Schultz

Meadows

Kothe

2022

Preprint

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Among the large and diverse collection of tRNA modifications, 7-methylguanosine is frequently found in the tRNA variable loop at position 46. This modification is introduced by the TrmB enzyme, which is conserved in bacteria and eukaryotes. Complementing the report of various phenotypes for different organisms lacking TrmB homologs, we report here hydrogen peroxide sensitivity for theEscherichia coli ΔtrmBknockout strain. To gain insight into the molecular mechanism of tRNA binding byE. coliTrmB in real-time, we developed a new assay based on introducing a 4-thiouridine modification at position 8 ofin vitrotranscribed tRNAPheenabling us to fluorescently labelled this unmodified tRNA. Using rapid kinetic stopped-flow measurements with this fluorescent tRNA, we examined the interaction of wild-type and single substitution variants of TrmB with tRNA. Our results reveal the role of SAM for rapid and stable tRNA binding, the rate-limiting nature of m7G46 catalysis for tRNA release, and the importance of residues R26, T127 and R155 across the entire surface of TrmB for tRNA binding.

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Section: Discussionmentioning

confidence: 99%

Section: Trmb Variant Binding To Trna Phementioning

confidence: 99%

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Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB

Schultz

Meadows

Kothe

2022

Preprint

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“…m7G modifications are commonly found in eubacteria, eukaryotes, and some archaea (Zhang et al, 2019a;Wiener and Schwartz, 2021) and are one of the few methylation modifications that introduce positively charged or amphiphilic ions into nucleobases (Figure 1B). m7G has a broad impact on mRNA, tRNA, and rRNA, playing a crucial function in various biological processes including transcriptional elongation, pre-mRNA splicing, and mRNA translation, as well as serving as an important indicator for disease diagnosis (Figure 2) (Alexandrov et al, 2002;Leulliot et al, 2008;Haag et al, 2015a;Lin et al, 2018;Liu et al, 2020c;Song et al, 2020;Blersch et al, 2021;Zhao et al, 2021).…”

Section: N7-methylguanosinementioning

confidence: 99%

The role of RNA modification in hepatocellular carcinoma

et al. 2022

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Hepatocellular carcinoma (HCC) is a highly mortal type of primary liver cancer. Abnormal epigenetic modifications are present in HCC, and RNA modification is dynamic and reversible and is a key post-transcriptional regulator. With the in-depth study of post-transcriptional modifications, RNA modifications are aberrantly expressed in human cancers. Moreover, the regulators of RNA modifications can be used as potential targets for cancer therapy. In RNA modifications, N6-methyladenosine (m6A), N7-methylguanosine (m7G), and 5-methylcytosine (m5C) and their regulators have important regulatory roles in HCC progression and represent potential novel biomarkers for the confirmation of diagnosis and treatment of HCC. This review focuses on RNA modifications in HCC and the roles and mechanisms of m6A, m7G, m5C, N1-methyladenosine (m1A), N3-methylcytosine (m3C), and pseudouridine (ψ) on its development and maintenance. The potential therapeutic strategies of RNA modifications are elaborated for HCC.

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“…In addition, METTL1-dependent m 7 G regulates miRNA structure and biogenesis ( 4 ). METTL1, localized on chromosome band 12q13, contains a conserved S-adenosylmethionine-binding motif and can be activated by loss of phosphorylation ( 5 , 6 ). Normally, METTL1 is expressed in the kidney, thyroid, adrenal, appendix, and 23 other tissues ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Analysis of METTL1 to Immunity and Stemness in Pan-Cancer

Gao

Zhang

et al. 2022

Front. Immunol.

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BackgroundPrevious studies have reported the effect of N7-methylguanosine (m7G) regulator methyltransferase like-1 protein (METTL1) in tumor initiation, metastasis, and chemosensitivity. However, the relationship between METTL1 and cancer immune infiltration is not validated and the prognostic significance of METTL1 in pan-cancer remains unclear.MethodsClinical parameters, including gender, age, lifetime, stage, and treatment response were analyzed to evaluate the prognostic significance of METTL1. To evaluate protein level of METTL1, the METTL1 activity was generated by single sample gene set enrichment analysis. The one-class logistic regression algorithm was used to calculate the stemness indices based on transcriptomics and methylation data of pan-cancer and pluripotent stem cells. The relationship between METTL1 expression or activity and tumor immune infiltration were analyzed to explore the significance of METTL1 in tumor immunotherapy. Meanwhile, the correlation between three immunotherapeutic biomarkers and METTL1 was investigated. Finally, to calculate the association between drug sensitivity and METTL1 expression, spearman correlation analysis was performed.ResultsMETTL1 was not intimately related to gender, age, tumor stage, or treatment outcome of the various cancers, but it displayed potential prognostic significance for evaluating patient survival. High METTL1 expression was related to tumor progression-relevant pathways. Moreover, METTL1 exhibited a distinct correlation with tumor immune microenvironment infiltration and stemness indices. In the anti-PD-L1 cohort, patients in treatment response group exhibited significantly higher METTL1 expression than those in the no/limited response group. Further analysis showed that tumor cell lines with higher METTL1 expression were more sensitive to drugs targeting chromatin histone methylation, ERK-MAPK and WNT signaling pathways.ConclusionThis study provides insight into the correlation of METTL1 with tumor immune infiltration and stemness in pan-cancer, revealing the significance of METTL1 for cancer progression and guiding more effective and generalized therapy strategies.

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Structural model of the M7G46 Methyltransferase TrmB in complex with tRNA

Cited by 10 publications

References 49 publications

Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB

Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB

The role of RNA modification in hepatocellular carcinoma

A Comprehensive Analysis of METTL1 to Immunity and Stemness in Pan-Cancer

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