Architecture of the yeast Elongator complex

Daudén, María I.; Kosiński, Jan; Kolaj-Robin, Olga; Desfosses, Ambroise; Ori, Alessandro; Faux, Céline; Hoffmann, N.A.; Onuma, Osita F; Breunig, Karin D.; Beck, Martin; Sachse, Carsten; Séraphin, Bertrand; Glatt, Sebastian; Müller, Christoph W.

doi:10.15252/embr.201643353

Cited by 76 publications

(107 citation statements)

References 81 publications

(116 reference statements)

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“…However, meanwhile a robust body of evidence indicates that its genuine role in yeast lies with tRNA modification rather than transcription elongation. Accordingly, Elongator binds tRNAs and modifies anticodon wobble uridine (U34) bases [8][9][10][11][12][13][14]. Strikingly, the methoxy-carbonyl-methyl-thio (mcm 5 s 2 ) modification at U34 in some of Elongator's tRNA substrates (including tRNA Glu ) allows anticodon cleavage by the -toxin tRNase [15].…”

Section: Introductionmentioning

confidence: 99%

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

Schaffrath¹,

Mehlgarten²,

Prochaska³

et al. 2017

Preprint

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Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex fromKluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin's action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein. From a kti12 mutant pool of zymocin survivors, we identify motifs in Kti12 that are functionally directly coupled to Elongator activity. In addition, shared requirement of U34 modifications for nonsense and missense tRNA suppression (SUP4; SOE1) strongly suggests that Kti12 and Elongator cooperate to assure proper tRNA functioning. We show that the Kti12 motifs are conserved in plant ortholog DRL1/ELO4 from Arabidopsis thaliana and seem to be involved in binding of cofactors (e.g. nucleotides, calmodulin). Elongator interaction defects triggered by mutations in these motifs correlate with phenotypes typical for loss of U34 modification. Thus, tRNA modification by Elongator appears to require physical contact with Kti12, and our preliminary data suggest that metabolic signals may affect proper communication between them.

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Section: Introductionmentioning

confidence: 99%

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

Schaffrath¹,

Mehlgarten²,

Prochaska³

et al. 2017

Preprint

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“…Despite their high similarity, there are differences in the independently proposed topological models of the Elongator complex . Firstly, in both studies the NT of Elp1 occupies the bottom part of the complex, while the position of the two Elp1 WD40 domains is slightly shifted.…”

Section: The Hexameric Elp456 Is Asymmetrically Attached To a Symmetrmentioning

confidence: 92%

“…Using an integrative workflow, the authors could reveal the complete subunit arrangement of the yeast Elongator complex (Fig. B) . The Elp456 subcomplex is attached to the CT and NT domains of Elp1, which occupy central positions also validated by antibody EM‐labeling.…”

Section: The Hexameric Elp456 Is Asymmetrically Attached To a Symmetrmentioning

confidence: 96%

“…The Elongator complex is formed by the binding of the Elp456 ring to one of the lobes of the Elp123 subcomplex . The EM structures of Elongator clearly resemble the Elp123 subcomplex in shape and dimensions (270 Å length and 180 Å height).…”

Section: The Hexameric Elp456 Is Asymmetrically Attached To a Symmetrmentioning

confidence: 97%

“…Elongator protein 2 is the second largest member of the Elongator proteins with a mass of approximately 90 kDa. Two independent and almost identical crystal structures (PDB ID http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4XFV and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5M2N) of yeast Elp2 have been solved at 3.2 and 2.8 Å resolution, respectively . The protein consists of two similar sized WD40 domains, which are slightly twisted with respect to each other and are stabilized by a so called ‘molecular velcro’, that connects the first 10 N‐terminal amino acid residues of Elp2 with the very C‐terminal β‐strand of blade 14 in the second WD40 domain.…”

Section: Elongator Harbors Six Individual Core Subunits and Is Contromentioning

confidence: 99%

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Structural asymmetry in the eukaryotic Elongator complex

et al. 2017

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Edited by Wilhelm JustNucleoside modifications in tRNA anticodons regulate ribosome dynamics during translation elongation and, thereby, fine-tune global protein synthesis rates. The highly conserved eukaryotic Elongator complex conducts specific C5-substitutions in tRNA wobble base uridines. It harbors two copies of each of its six individual subunits, which are all equally important for its activity. Here, we summarize recent developments focusing on the architecture of the Elongator complex, showing an asymmetric subunit arrangement, and its functional implications. In addition, we discuss the role of its proposed active site, its individual subunits and temporarily associated regulatory factors. Finally, we aim to provide mechanistic explanations for the link between mutations in Elongator subunits and the onset of several severe human pathologies.

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tRNAModification by Elongator Protein 3 (Elp3)

Lin

Glatt

2018

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Elongator 3 (Elp3) represents the enzymatically active subunit of the multisubunit Elongator complex that catalyzes the first step of the 5‐methoxycarbonylmethyl and 5‐carbamoylmethyl modification reaction at uridine bases in the wobble position of tRNAs. These modifications are essential for accurate protein translation rates and proteome homeostasis, and their loss is detrimental, leading to cellular dysfunctions, neurodegenerative diseases, and cancers. The electron microscopy structure of the Elongator and the crystal structure of Elp3 have recently been resolved, but details of the enzymatic reaction still remain elusive. One copy of Elp3 is located in each center of the two Elp123 lobes, and unlike other known modifying enzymes, Elp3 consists of two functional domains, namely radical S ‐adenosyl methionine and lysine acetyltransferase domains. The SAM domain harbors an iron–sulfur (Fe–S) cluster, which is essential for the integrity and activity of the complex. In addition, Elp3 coordinates zinc and interacts with Kti11, a regulatory factor that coordinates iron and zinc, most likely acting as an electron donor for the respective Fe–S cluster of Elp3. Through the unique combination and interplay of its two domains, Elp3 is able to cleave SAM, generate necessary deoxy radicals, and transfer an acetyl radical from acetyl‐CoA to C5 of U 34 .

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Architecture of the yeast Elongator complex

Cited by 76 publications

References 81 publications

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

Use of a Yeast TRNase Killer Toxin to Diagnose Kti12 Motifs Required for TRNA Modification by Elongator

Structural asymmetry in the eukaryotic Elongator complex

tRNAModification by Elongator Protein 3 (Elp3)

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