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  • 1.
    Atkinson, Gemma C.
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia .
    Kuzmenko, Anton
    University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia & Department of Molecular Biology, Faculty of Biology, Moscow State University, Moscow, Russia .
    Chicherin, Ivan
    Department of Molecular Biology, Faculty of Biology, Moscow State University, Moscow, Russia.
    Soosaar, Axel
    University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia .
    Tenson, Tanel
    University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia .
    Carr, Martin
    School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, UK.
    Kamenski, Piotr
    Department of Molecular Biology, Faculty of Biology, Moscow State University, Moscow, Russia .
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia .
    An evolutionary ratchet leading to loss of elongation factors in eukaryotes2014In: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 14, p. 35-Article in journal (Refereed)
    Abstract [en]

    Background: The GTPase eEF1A is the eukaryotic factor responsible for the essential, universal function of aminoacyl-tRNA delivery to the ribosome. Surprisingly, eEF1A is not universally present in eukaryotes, being replaced by the paralog EFL independently in multiple lineages. The driving force behind this unusually frequent replacement is poorly understood. Results: Through sequence searching of genomic and EST databases, we find a striking association of eEF1A replacement by EFL and loss of eEF1A's guanine exchange factor, eEF1Ba, suggesting that EFL is able to spontaneously recharge with GTP. Sequence conservation and homology modeling analyses indicate several sequence regions that may be responsible for EFL's lack of requirement for eEF1Ba. Conclusions: We propose that the unusual pattern of eEF1A, eEF1Ba and EFL presence and absence can be explained by a ratchet-like process: if either eEF1A or eEF1Ba diverges beyond functionality in the presence of EFL, the system is unable to return to the ancestral, eEF1A:eEFBa-driven state.

  • 2.
    Atkinson, Gemma Catherine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Nooruse 1, Tartu, 50411, Estonia.
    The evolutionary and functional diversity of classical and lesser-known cytoplasmic and organellar translational GTPases across the tree of life2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 78Article in journal (Refereed)
    Abstract [en]

    Background: The ribosome translates mRNA to protein with the aid of a number of accessory protein factors. Translational GTPases (trGTPases) are an integral part of the 'core set' of essential translational factors, and are some of the most conserved proteins across life. This study takes advantage of the wealth of available genomic data, along with novel functional information that has come to light for a number of trGTPases to address the full evolutionary and functional diversity of this superfamily across all domains of life. 

    Results: Through sensitive sequence searching combined with phylogenetic analysis, 57 distinct subfamilies of trGTPases are identified: 14 bacterial, 7 archaeal and 35 eukaryotic (of which 21 are known or predicted to be organellar). The results uncover the functional evolution of trGTPases from before the last common ancestor of life on earth to the current day. 

    Conclusions: While some trGTPases are universal, others are limited to certain taxa, suggesting lineage-specific translational control mechanisms that exist on a base of core factors. These lineage-specific features may give organisms the ability to tune their translation machinery to respond to their environment. Only a fraction of the diversity of the trGTPase superfamily has been subjected to experimental analyses; this comprehensive classification brings to light novel and overlooked translation factors that are worthy of further investigation.

  • 3. Crowe-McAuliffe, Caillan
    et al.
    Graf, Michael
    Huter, Paul
    Takada, Hiraku
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Abdelshahid, Maha
    Novácek, Jirí
    Murina, Victoriia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
    Wilson, Daniel N.
    Structural basis for antibiotic resistance mediated by the Bacillus subtilis ABCF ATPase VmlR2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 36, p. 8978-8983Article in journal (Refereed)
    Abstract [en]

    Many Gram-positive pathogenic bacteria employ ribosomal protection proteins (RPPs) to confer resistance to clinically important antibiotics. In Bacillus subtilis, the RPP VmlR confers resistance to lincomycin (Lnc) and the streptogramin A (SA) antibiotic virginiamycin M (VgM). VmlR is an ATP-binding cassette (ABC) protein of the F type, which, like other antibiotic resistance (ARE) ABCF proteins, is thought to bind to antibiotic-stalled ribosomes and promote dissociation of the drug from its binding site. To investigate the molecular mechanism by which VmlR confers antibiotic resistance, we have determined a cryo-electron microscopy (cryo-EM) structure of an ATPase-deficient B. subtilis VmlR-EQ(2) mutant in complex with a B. subtilis ErmDL-stalled ribosomal complex (SRC). The structure reveals that VmlR binds within the E site of the ribosome, with the antibiotic resistance domain (ARD) reaching into the peptidyltransferase center (PTC) of the ribosome and a C-terminal extension (CTE) making contact with the small subunit (SSU). To access the PTC, VmlR induces a conformational change in the P-site tRNA, shifting the acceptor arm out of the PTC and relocating the CCA end of the P-site tRNA toward the A site. Together with microbiological analyses, our study indicates that VmlR allosterically dissociates the drug from its ribosomal binding site and exhibits specificity to dislodge VgM, Lnc, and the pleuromutilin tiamulin (Tia), but not chloramphenicol (Cam), linezolid (Lnz), nor the macrolide erythromycin (Ery).

  • 4.
    Hauryliuk, Vasili
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Small Alarmone Synthetases as novel bacterial RNA-binding proteins2017In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 14, no 12, p. 1695-1699Article, review/survey (Refereed)
    Abstract [en]

    The alarmone nucleotides guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), collectively referred to as (p)ppGpp, are key regulators of bacterial growth, stress adaptation, antibiotic tolerance and pathogenicity. We have recently shown that the Small Alarmone Synthetase (SAS) RelQ from the Gram-positive pathogen Enterococcus faecalis has an RNA-binding activity (Beljantseva et al. 2017). RelQ's activities as an enzyme and as an RNA-binding protein are mutually incompatible: binding of single-stranded RNA potently inhibits (p)ppGpp synthesis in a sequence-specific manner, and RelQ's enzymatic activity destabilizes the RNA: RelQ complex. RelQ's allosteric regulator, pppGpp, destabilizes RNA binding and activates RelQ's enzymatic activity. Since SAS enzymes are widely distributed in bacteria, and, as has been discovered recently, are also mobilized by phages (Dedrick et al. 2017), RNA binding to SASs could be a widespread mechanism. The initial discovery raises numerous questions regarding RNA-binding function of the SAS enzymes: What is the molecular mechanism underlying the incompatibility of RNA: SAS complex formation with pppGpp binding and (p)ppGpp synthesis? What are the RNA targets in living cells? What is the regulatory output of the system - (p)ppGpp synthesis, modulation of RNA structure and function, or both?

  • 5.
    Hauryliuk, Vasili
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Murakami, Katsuhiko S.
    Department of Biochemistry and Molecular Biology, Center for RNA Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
    Tenson, Tanel
    Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Gerdes, Kenn
    Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
    Recent functional insights into the role of (p)ppGpp in bacterial physiology2015In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 13, no 5, p. 298-309Article, review/survey (Refereed)
    Abstract [en]

    The alarmones guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p) ppGpp) are involved in regulating growth and several different stress responses in bacteria. In recent years, substantial progress has been made in our understanding of the molecular mechanisms of (p) ppGpp metabolism and (p) ppGpp-mediated regulation. In this Review, we summarize these recent insights, with a focus on the molecular mechanisms governing the activity of the RelA/SpoT homologue (RSH) proteins, which are key players that regulate the cellular levels of (p) ppGpp. We also discuss the structural basis of transcriptional regulation by (p) ppGpp and the role of (p) ppGpp in GTP metabolism and in the emergence of bacterial persisters.

  • 6.
    Kasari, Villu
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Margus, Tonu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). 3 University of Tartu, Institute of Technology, Tartu, Estonia.
    Ribosome profiling analysis of eEF3-depleted Saccharomyces cerevisiae2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3037Article in journal (Refereed)
    Abstract [en]

    In addition to the standard set of translation factors common in eukaryotic organisms, protein synthesis in the yeast Saccharomyces cerevisiae requires an ABCF ATPase factor eEF3, eukaryotic Elongation Factor 3. eEF3 is an E-site binder that was originally identified as an essential factor involved in the elongation stage of protein synthesis. Recent biochemical experiments suggest an additional function of eEF3 in ribosome recycling. We have characterised the global effects of eEF3 depletion on translation using ribosome profiling. Depletion of eEF3 results in decreased ribosome density at the stop codon, indicating that ribosome recycling does not become rate limiting when eEF3 levels are low. Consistent with a defect in translation elongation, eEF3 depletion causes a moderate redistribution of ribosomes towards the 5' part of the open reading frames. We observed no E-site codon-or amino acid-specific ribosome stalling upon eEF3 depletion, supporting its role as a general elongation factor. Surprisingly, depletion of eEF3 leads to a relative decrease in P-site proline stalling, which we hypothesise is a secondary effect of generally decreased translation and/or decreased competition for the E-site with eIF5A.

  • 7.
    Kasari, Villu
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Pochopien, Agnieszka A.
    Margus, Tonu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Murina, Victoriia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Turnbull, Kathryn Jane
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Zhou, Yang
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Graf, Michael
    Novacek, Jiri
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wilson, Daniel N.
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, 50411 Tartu, Estonia.
    A role for the Saccharomyces cerevisiae ABCF protein New1 in translation termination/recycling2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 16, p. 8807-8820Article in journal (Refereed)
    Abstract [en]

    Translation is controlled by numerous accessory proteins and translation factors. In the yeast Saccharomyces cerevisiae, translation elongation requires an essential elongation factor, the ABCF ATPase eEF3. A closely related protein, New1, is encoded by a non-essential gene with cold sensitivity and ribosome assembly defect knock-out phenotypes. Since the exact molecular function of New1 is unknown, it is unclear if the ribosome assembly defect is direct, i.e. New1 is a bona fide assembly factor, or indirect, for instance due to a defect in protein synthesis. To investigate this, we employed yeast genetics, cryo-electron microscopy (cryo-EM) and ribosome profiling (Ribo-Seq) to interrogate the molecular function of New1. Overexpression of New1 rescues the inviability of a yeast strain lacking the otherwise strictly essential translation factor eEF3. The structure of the ATPase-deficient (EQ2) New1 mutant locked on the 80S ribosome reveals that New1 binds analogously to the ribosome as eEF3. Finally, Ribo-Seq analysis revealed that loss of New1 leads to ribosome queuing upstream of 3′-terminal lysine and arginine codons, including those genes encoding proteins of the cytoplasmic translational machinery. Our results suggest that New1 is a translation factor that fine-tunes the efficiency of translation termination or ribosome recycling.

  • 8. Kuzmenko, Anton
    et al.
    Derbikova, Ksenia
    Salvatori, Roger
    Tankov, Stoyan
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). University of Tartu, Institute of Technology, Tartu, Estonia.
    Tenson, Tanel
    Ott, Martin
    Kamenski, Piotr
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). University of Tartu, Institute of Technology, Tartu, Estonia.
    Aim-less translation: loss of Saccharomyces cerevisiae mitochondrial translation initiation factor mIF3/Aim23 leads to unbalanced protein synthesis2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 18749Article in journal (Refereed)
    Abstract [en]

    The mitochondrial genome almost exclusively encodes a handful of transmembrane constituents of the oxidative phosphorylation (OXPHOS) system. Coordinated expression of these genes ensures the correct stoichiometry of the system's components. Translation initiation in mitochondria is assisted by two general initiation factors mIF2 and mIF3, orthologues of which in bacteria are indispensible for protein synthesis and viability. mIF3 was thought to be absent in Saccharomyces cerevisiae until we recently identified mitochondrial protein Aim23 as the missing orthologue. Here we show that, surprisingly, loss of mIF3/Aim23 in S. cerevisiae does not indiscriminately abrogate mitochondrial translation but rather causes an imbalance in protein production: the rate of synthesis of the Atp9 subunit of F1F0 ATP synthase (complex V) is increased, while expression of Cox1, Cox2 and Cox3 subunits of cytochrome c oxidase (complex IV) is repressed. Our results provide one more example of deviation of mitochondrial translation from its bacterial origins.

  • 9.
    Murina, Victoriia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kasari, Marje
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest2018In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 7, p. 3753-3763Article in journal (Refereed)
    Abstract [en]

    Several ATPases in the ATP-binding cassette F (ABCF) family confer resistance to macrolides, lincosamides and streptogramins (MLS) antibiotics. MLS are structurally distinct classes, but inhibit a common target: the peptidyl transferase (PTC) active site of the ribosome. Antibiotic resistance (ARE) ABCFs have recently been shown to operate through direct ribosomal protection, but the mechanistic details of this resistance mechanism are lacking. Using a reconstituted translational system, we dissect the molecular mechanism of Staphylococcus haemolyticus VgaA(LC) and Enterococcus faecalis LsaA on the ribosome. We demonstrate that VgaA(LC) is an NTPase that operates as a molecular machine strictly requiring NTP hydrolysis (not just NTP binding) for antibiotic protection. Moreover, when bound to the ribosome in the NTP-bound form, hydrolytically inactive EQ(2) ABCF ARE mutants inhibit peptidyl transferase activity, suggesting a direct interaction between the ABCF ARE and the PTC. The likely structural candidate responsible for antibiotic displacement by wild type ABCF AREs, and PTC inhibition by the EQ(2) mutant, is the extended inter-ABC domain linker region. Deletion of the linker region renders wild type VgaA(LC) inactive in antibiotic protection and the EQ(2) mutant inactive in PTC inhibition.

  • 10.
    Murina, Victoriia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kasari, Marje
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Takada, Hiraku
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hinnu, Mariliis
    Kumar Saha, Chayan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grimshaw, James W.
    Seki, Takahiro
    Reith, Michael
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Putrins, Marta
    Tenson, Tanel
    Strahl, Henrik
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Tartu, Estonia.
    Atkinson, Gemma Catherine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    ABCF ATPases Involved in Protein Synthesis, Ribosome Assembly and Antibiotic Resistance: Structural and Functional Diversification across the Tree of Life2019In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 431, no 18, p. 3568-3590Article in journal (Refereed)
    Abstract [en]

    Within the larger ABC superfamily of ATPases, ABCF family members eEF3 in Saccharomyces cerevisiae and EttA in Escherichia coli have been found to function as ribosomal translation factors. Several other ABCFs including biochemically characterized VgaA, LsaA and MsrE confer resistance to antibiotics that target the peptidyl transferase center and exit tunnel of the ribosome. However, the diversity of ABCF subfamilies, the relationships among subfamilies and the evolution of antibiotic resistance (ARE) factors from other ABCFs have not been explored. To address this, we analyzed the presence of ABCFs and their domain architectures in 4505 genomes across the tree of life. We find 45 distinct subfamilies of ABCFs that are widespread across bacterial and eukaryotic phyla, suggesting that they were present in the last common ancestor of both. Surprisingly, currently known ARE ABCFs are not confined to a distinct lineage of the ABCF family tree, suggesting that ARE can readily evolve from other ABCF functions. Our data suggest that there are a number of previously unidentified ARE ABCFs in antibiotic producers and important human pathogens. We also find that ATPase-deficient mutants of all four E. coli ABCFs (EttA, YbiT, YheS and Uup) inhibit protein synthesis, indicative of their ribosomal function, and demonstrate a genetic interaction of ABCFs Uup and YheS with translational GTPase BipA involved in assembly of the 50S ribosome subunit. Finally, we show that the ribosome-binding resistance factor VmlR from Bacillus subtilis is localized to the cytoplasm, ruling out a role in antibiotic efflux.

  • 11.
    Seibt, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Aung, Kyaw Min
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ishikawa, Takahiko
    Sjöström, Annika
    Atkinson, Gemma C.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wai, Sun Nyunt
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Shingler, Victoria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Elevated levels of VCA0117 in response to external signals activates type VI secretion in Vibrio cholerae A1552Manuscript (preprint) (Other academic)
  • 12. Sothiselvam, Shanmugapriya
    et al.
    Liu, Bo
    Han, Wei
    Ramu, Haripriya
    Klepacki, Dorota
    Atkinson, Gemma Catherine
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Brauer, Age
    Remm, Maido
    Tenson, Tanel
    Schulten, Klaus
    Vazquez-Laslop, Nora
    Mankin, Alexander S
    Macrolide antibiotics allosterically predispose the ribosome for translation arrest2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 27, p. 9804-9809Article in journal (Refereed)
    Abstract [en]

    Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

  • 13. Starosta, Agata L.
    et al.
    Lassak, Jürgen
    Peil, Lauri
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu, Estonia.
    Virumäe, Kai
    Tenson, Tanel
    Remme, Jaanus
    Jung, Kirsten
    Wilson, Daniel N.
    Translational stalling at polyproline stretches is modulated by the sequence context upstream of the stall site2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 16, p. 10711-10719Article in journal (Refereed)
    Abstract [en]

    The polymerization of amino acids into proteins occurs on ribosomes, with the rate influenced by the amino acids being polymerized. The imino acid proline is a poor donor and acceptor for peptide-bond formation, such that translational stalling occurs when three or more consecutive prolines (PPP) are encountered by the ribosome. In bacteria, stalling at PPP motifs is rescued by the elongation factor P (EF-P). Using SILAC mass spectrometry of Escherichia coli strains, we identified a subset of PPP-containing proteins for which the expression patterns remained unchanged or even appeared up-regulated in the absence of EF-P. Subsequent analysis using in vitro and in vivo reporter assays revealed that stalling at PPP motifs is influenced by the sequence context upstream of the stall site. Specifically, the presence of amino acids such as Cys and Thr preceding the stall site suppressed stalling at PPP motifs, whereas amino acids like Arg and His promoted stalling. In addition to providing fundamental insight into the mechanism of peptide-bond formation, our findings suggest how the sequence context of polyproline-containing proteins can be modulated to maximize the efficiency and yield of protein production.

  • 14. Starosta, Agata L
    et al.
    Lassak, Jürgen
    Peil, Lauri
    Atkinson, Gemma C
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu 50090, Estonia.
    Woolstenhulme, Christopher J.
    Virumäe, Kai
    Buskirk, Allen
    Tenson, Tanel
    Remme, Jaanus
    Jung, Kirsten
    Wilson, Daniel N.
    A conserved proline triplet in Val-tRNA synthetase and the origin of elongation factor P2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, no 2, p. 476-483Article in journal (Refereed)
    Abstract [en]

    Bacterial ribosomes stall on polyproline stretches and require the elongation factor P (EF-P) to relieve the arrest. Yet it remains unclear why evolution has favored the development of EF-P rather than selecting against the occurrence of polyproline stretches in proteins. We have discovered that only a single polyproline stretch is invariant across all domains of life, namely a proline triplet in ValS, the tRNA synthetase, that charges tRNA(Val) with valine. Here, we show that expression of ValS in vivo and in vitro requires EF-P and demonstrate that the proline triplet located in the active site of ValS is important for efficient charging of tRNA(Val) with valine and preventing formation of mischarged Thr-tRNA(Val) as well as efficient growth of E. coli in vivo. We suggest that the critical role of the proline triplet for ValS activity may explain why bacterial cells coevolved the EF-P rescue system.

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