Mechanism of activation of methyltransferases involved in translation by the Trm112 ‘hub’ protein

Liger, Dominique; Mora, Liliana; Lazar, Noureddine; Figaro, Sabine; Henri, Julien; Scrima, Nathalie; Buckingham, Richard H.; Tilbeurgh, Herman van; Heurgué-Hamard, Valérie; Graille, Marc

doi:10.1093/nar/gkr176

Cited by 67 publications

(120 citation statements)

References 62 publications

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“…Trm112 increases the solubility of several of its partners, including Trm9 and Mtq2 (32,36) and, as established here, Bud23, suggesting that it is required for optimal folding of this group of class I MTase apoenzymes. Trm112 interaction with Mtq2, and most probably Trm9, buries a large hydrophobic solvent-accessible region, providing a rationale for the increased solubility observed upon complex formation and the resistance of complexes to high-ionic-strength treatment (32).…”

Section: Discussionsupporting

confidence: 65%

“…Trm112 interaction with Mtq2, and most probably Trm9, buries a large hydrophobic solvent-accessible region, providing a rationale for the increased solubility observed upon complex formation and the resistance of complexes to high-ionic-strength treatment (32). These properties are shared by the Bud23-Trm112 complex, which is resistant to high salt washes in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…The structure of the S. cerevisiae Bud23-Trm112 model was obtained by superimposing the coordinates of the S. cerevisiae Trm112 crystal structure (15) and the Bud23 model onto the corresponding parts from our recently solved Encephalitozoon cuniculi Mtq2-Trm112 crystal structure (32). The stereochemistry of this Bud23-Trm112 model was further optimized using energy minimization as implemented in the CNS software so as to avoid steric clashes between the two partners (1).…”

Section: Methodsmentioning

confidence: 99%

“…Trm112 is a small zinc finger protein of 15 kDa which acts as a coactivator of several class I S-adenosyl-L-methionine (SAM)-dependent MTases (15,32,36,49,58). To date, Trm112 is known to interact with, and to activate, three MTases, namely, Mtq2, Trm9, and Trm11, all related to ribosome function.…”

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confidence: 99%

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Trm112 Is Required for Bud23-Mediated Methylation of the 18S rRNA at Position G1575

Figaro

Wacheul

Schillewaert

et al. 2012

Molecular and Cellular Biology

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116

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Posttranscriptional and posttranslational modification of macromolecules is known to fine-tune their functions. Trm112 is unique, acting as an activator of both tRNA and protein methyltransferases. Here we report that in Saccharomyces cerevisiae, Trm112 is required for efficient ribosome synthesis and progression through mitosis. Trm112 copurifies with pre-rRNAs and with multiple ribosome synthesis trans-acting factors, including the 18S rRNA methyltransferase Bud23. Consistent with the known mechanisms of activation of methyltransferases by Trm112, we found that Trm112 interacts directly with Bud23 in vitro and that it is required for its stability in vivo. Consequently, trm112⌬ cells are deficient for Bud23-mediated 18S rRNA methylation at position G1575 and for small ribosome subunit formation. Bud23 failure to bind nascent preribosomes activates a nucleolar surveillance pathway involving the TRAMP complexes, leading to preribosome degradation. Trm112 is thus active in rRNA, tRNA, and translation factor modification, ideally placing it at the interface between ribosome synthesis and function.A ctively growing budding yeast cells produce an average of 33 ribosomes per second, which is considerable (61). Besides the synthesis of its constituents, i.e., 79 ribosomal proteins and 4 rRNAs, ribogenesis involves a large number of so-called transacting factors, including proteins and small nucleolar RNAs (13, 56). These interact only transiently with preribosomes and are required for pre-rRNA processing (i.e., cleavages), pre-rRNA modification, and preribosome assembly and transport.Ribosome synthesis is initiated in the nucleolus, a highly dynamic specialized subcompartment of the nucleus organized around clusters of actively transcribed rRNA genes (60). There, RNA polymerase I produces a 35S/47S (in yeasts and humans, respectively) primary transcript which is processed through a complex succession of endo-and exoribonucleolytic cleavages into three of the four mature rRNAs, the 18S, 5.8S, and 25S/28S rRNAs. The fourth rRNA, 5S, is independently transcribed by RNA polymerase III. Ribosome maturation starts cotranscriptionally in the nucleolus, progresses in the nucleoplasm until preribosomes reach the nuclear pore complex, and is finalized in the cytoplasm. Cytoplasmic maturation steps consisting of pre-rRNA processing and structural reorganization result in the assembly of prominent ribosomal structures, such as the "beak" of the small subunit (SSU) and the "stalk" of the large subunit, and are a prerequisite to the acquisition of functionality (43).It is not clear how the various facets of ribosome synthesis are integrated with ribosome function. However, there is growing evidence that such coordination exists. For the small subunit, recent cryoelectron microscopy (cryo-EM) maps of late pre-40S subunits indicate that the binding of trans-acting factors literally mask functional sites, preventing premature translation initiation (57). For the large subunit, trans-acting factors that resemble ribosomal proteins (suc...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Trm112 Is Required for Bud23-Mediated Methylation of the 18S rRNA at Position G1575

Figaro

Wacheul

Schillewaert

et al. 2012

Molecular and Cellular Biology

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116

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“…7). Although a crystal structure for the Bud23/ Trm112 complex is not yet available, the complex can be modeled on the structure of Trm112 in complex with a related methyltransferase, Mtq2 (46). Two of the residues that we identified as specific for Ecm16 interaction (D94 and D99) map to the predicted Trm112 binding surface.…”

Section: Functional and Physical Interaction Between Bud23 And Ecm16mentioning

confidence: 99%

Physical and Functional Interaction between the Methyltransferase Bud23 and the Essential DEAH-Box RNA Helicase Ecm16

Sardana

Zhu

Gill

et al. 2014

Molecular and Cellular Biology

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The small ribosomal subunit assembles cotranscriptionally on the nascent primary transcript. Cleavage at site A2 liberates the pre-40S subunit. We previously identified Bud23 as a conserved eukaryotic methyltransferase that is required for efficient cleavage at A2. Here, we report that Bud23 physically and functionally interacts with the DEAH-box RNA helicase Ecm16 (also known as Dhr1). Ecm16 is also required for cleavage at A2. We identified mutations in ECM16 that suppressed the growth and A2 cleavage defects of a bud23⌬ mutant. RNA helicases often require protein cofactors to provide substrate specificity. We used yeast (Saccharomyces cerevisiae) two-hybrid analysis to map the binding site of Bud23 on Ecm16. Despite the physical and functional interaction between these factors, mutations that disrupted the interaction, as assayed by two-hybrid analysis, did not display a growth defect. We previously identified mutations in UTP2 and UTP14 that suppressed bud23⌬. We suggest that a network of protein interactions may mask the loss of interaction that we have defined by two-hybrid analysis. A mutation in motif I of Ecm16 that is predicted to impair its ability to hydrolyze ATP led to accumulation of Bud23 in an ϳ45S particle containing Ecm16. Thus, Bud23 enters the pre-40S pathway at the time of Ecm16 function.

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Assessing Structural Predictions of Protein–Protein Recognition: The CAPRI Experiment

Janin

Wodak

Lensink

et al. 2015

Reviews in Computational Chemistry

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Mechanism of activation of methyltransferases involved in translation by the Trm112 ‘hub’ protein

Cited by 67 publications

References 62 publications

Trm112 Is Required for Bud23-Mediated Methylation of the 18S rRNA at Position G1575

Trm112 Is Required for Bud23-Mediated Methylation of the 18S rRNA at Position G1575

Physical and Functional Interaction between the Methyltransferase Bud23 and the Essential DEAH-Box RNA Helicase Ecm16

Assessing Structural Predictions of Protein–Protein Recognition: The CAPRI Experiment

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