Structural asymmetry in the eukaryotic Elongator complex

Daudén, María I.; Jaciuk, Marcin; Müller, Christoph W.; Glatt, Sebastian

doi:10.1002/1873-3468.12865

Cited by 29 publications

(23 citation statements)

References 101 publications

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“…Those chemically rather complicated tRNA modifications are introduced by a cascade of enzymes, including the Elongator complex (Huang et al 2005b ; Dauden et al 2018 ), methyltransferases Trm9-Trm112/ALKBH8 (Studte et al 2008 ; Songe-Møller et al 2010 ; van Tran et al 2018 ), and the Uba4/Urm1 thiolation pathway (Leidel et al 2009 ; Noma et al 2009 ). Despite the creation of a toxin-target site, these tRNA modifications are genuinely required for maintaining proper translation speed and preventing from co-translational protein misfolding (Nedialkova and Leidel 2015 ; Ranjan and Rodnina 2016 ; Goffena et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the creation of a toxin-target site, these tRNA modifications are genuinely required for maintaining proper translation speed and preventing from co-translational protein misfolding (Nedialkova and Leidel 2015 ; Ranjan and Rodnina 2016 ; Goffena et al 2018 ). The lack of these anticodon modifications in humans causes various pathophysiologies, including severe neurodegenerative diseases (Close et al 2006 ; Chaverra et al 2017 ; Dauden et al 2018 ; Kojic et al 2018 ; Hawer et al 2018 ; Shaheen et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Fungal Kti12 proteins display unusual linker regions and unique ATPase p-loops

et al. 2020

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Kti12 (Kluyveromyces lactis toxin insensitive 12) is an evolutionary highly conserved ATPase, crucial for the tRNA-modification activity of the eukaryotic Elongator complex. The protein consists of an N-terminal ATPase and a C-terminal tRNA-binding domain, which are connected by a flexible linker. The precise role of the linker region and its involvement in the communication between the two domains and their activities remain elusive. Here, we analyzed all available Kti12 protein sequences and report the discovery of a subset of Kti12 proteins with abnormally long linker regions. These Kti12 proteins are characterized by a co-occurring lysine to leucine substitution in their Walker A motif, previously thought to be invariable. We show that the K14L substitution lowers the affinity to ATP, but does not affect the catalytic activity of Kti12 at high ATP concentrations. We compare the activity of mutated variants of Kti12 in vitro with complementation assays in vivo in yeast. Ultimately, we compared Kti12 to other known p-loop ATPase family members known to carry a similar deviant Walker A motif. Our data establish Kti12 of Eurotiomycetes as an example of eukaryotic ATPase harboring a significantly deviating but still functional Walker A motif.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fungal Kti12 proteins display unusual linker regions and unique ATPase p-loops

et al. 2020

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“…The first step in formation of the xm 5 groups is dependent on the Elongator complex, which is composed of two sets of the six Elp proteins (Elp1-Elp6) (Dauden et al 2017(Dauden et al , 2018Huang et al 2005;Johansson et al 2018;Kolaj-Robin and Seraphin 2017;Setiaputra et al 2017;Winkler et al 2001). Elongator is thought to catalyze the formation of a cm 5 U 34 residue, which is then further modified by additional enzymes.…”

Section: Introductionmentioning

confidence: 99%

SSD1 modifies phenotypes of Elongator mutants

Byström

Johansson

2019

Curr Genet

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The translational decoding properties of tRNAs are influenced by post-transcriptional modification of nucleosides in their anticodon region. The Elongator complex promotes the first step in the formation of 5-methoxycarbonylmethyl (mcm 5), 5-methoxycarbonylhydroxymethyl (mchm 5), and 5-carbamoylmethyl (ncm 5) groups on wobble uridine residues in eukaryotic cytosolic tRNAs. Elongator mutants in yeast, worms, plants, mice, and humans not only show a tRNA modification defect, but also a diverse range of additional phenotypes. Even though the phenotypes are almost certainly caused by the reduced functionality of the hypomodified tRNAs in translation, the basis for specific phenotypes is not well understood. Here, we discuss the recent finding that the phenotypes of Saccharomyces cerevisiae Elongator mutants are modulated by the genetic background. This background-effect is largely due to the allelic variation at the SSD1 locus, which encodes an mRNA-binding protein involved in post-transcriptional regulation of gene expression. A nonsense ssd1 allele is found in several wild-type laboratory strains and the presence of this allele aggravates the stress-induced phenotypes of Elongator mutants. Moreover, other phenotypes, such as the histone acetylation and telomeric gene silencing defects, are dependent on the mutant ssd1 allele. Thus, SSD1 is a genetic modifier of the phenotypes of Elongator-deficient yeast cells.

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“…Uridines present at the wobble position in eukaryotic cytoplasmic tRNAs often harbor a 5methoxycarbonylmethyl (mcm 5 ) or 5-carbamoylmethyl (ncm 5 ) side-chain and sometimes also a 2-thio (s 2 ) or 2ʹ-O-methyl group [3,4]. The first step in the synthesis of the mcm 5 and ncm 5 side-chains requires the Elongator complex, which is composed of six Elp proteins (Elp1-Elp6) [5][6][7][8][9]. Elongator is thought to catalyze the addition of a carboxymethyl (cm) group to the 5-position of the uridine which is then converted to mcm 5 by the Trm9/Trm112 complex or to ncm 5 by a yet unidentified mechanism [5,[8][9][10][11][12]].…”

Section: Introductionmentioning

confidence: 99%

SSD1suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications

Byström

Johansson

2019

Preprint

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24The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm 5 ) and 25 5-carbamoylmethyl (ncm 5 ) side-chains on uridines at the wobble position of cytosolic 26 eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of 27 Elongator not only leads to the lack of mcm 5 /ncm 5 groups in tRNAs, but also a wide 28 variety of phenotypes. Although the phenotypes are most likely caused by a 29 translational defect induced by reduced functionality of the hypomodified tRNAs, the 30 mechanism(s) underlying individual phenotypes are poorly understood. In this study, 31 we show that the genetic background modulates the phenotypes induced by the lack 32 of mcm 5 /ncm 5 groups in Saccharomyces cerevisiae. We show that the stress-33 induced growth defects of Elongator mutants are stronger in the W303 than in the 34 closely related S288C genetic background and that the phenotypic differences are 35 caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. 36 Moreover, the mutant ssd1 allele found in W303 cells is required for the reported 37 histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. 38The difference at the SSD1 locus also partially explains why the simultaneous lack of 39 mcm 5 and 2-thio groups at wobble uridines is lethal in the W303 but not in the 40 S288C background. Collectively, our results demonstrate that the SSD1 locus 41 modulates phenotypes induced by the lack of Elongator-dependent tRNA 42 modifications. 43 44 Author Summary 45 Modified nucleosides in the anticodon region of tRNAs are important for the 46 efficiency and fidelity of translation. The Elongator complex promotes formation of 47 3 48 In yeast, plants, worms, mice and humans, mutations in genes for Elongator 49 subunits lead to a wide variety of different phenotypes. Here, we show that the 50 genetic background modulates the phenotypic consequences of the inactivation of 51 budding yeast Elongator. This background effect is largely a consequence of a 52 polymorphism at the SSD1 locus, encoding a RNA binding protein that influences 53 translation, stability and/or localization of mRNAs. We show that several phenotypes 54 reported for yeast Elongator mutants are either significantly stronger or only 55 detectable in strains harboring a mutant ssd1 allele. Thus, SSD1 is a suppressor of 56 the phenotypes induced by the hypomodification of tRNAs. 4 57 104 to influence the cell wall remodeling that occurs upon stress, e.g. the mRNA-binding 105 protein Ssd1. Ssd1 has been reported to bind and influence the translation, stability 106 and/or localization of a subset of cellular mRNAs of which many encode proteins 6 107 important for cell wall biosynthesis and remodeling, [26-31]. The wild-type SSD1 108 gene was originally identified as a suppressor of the lethality induced by a deletion of 109 the SIT4 gene, which encodes a phosphatase involved in a wide range of cellular 110 processes [32]. The study also led to the finding that some wild-type S. cerevisia...

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Structural asymmetry in the eukaryotic Elongator complex

Cited by 29 publications

References 101 publications

Fungal Kti12 proteins display unusual linker regions and unique ATPase p-loops

Fungal Kti12 proteins display unusual linker regions and unique ATPase p-loops

SSD1 modifies phenotypes of Elongator mutants

SSD1suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications

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