peptide elongation factor 2

Summary

Summary: Peptide Elongation Factor 2 catalyzes the translocation of peptidyl-tRNA from the A site to the P site of eukaryotic ribosomes by a process linked to the hydrolysis of GTP to GDP.

Top Publications

  1. Hizli A, Chi Y, Swanger J, Carter J, Liao Y, Welcker M, et al. Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent kinase 2 regulates its inhibition by eEF2 kinase. Mol Cell Biol. 2013;33:596-604 pubmed publisher
    ..Because all known eEF2 regulation is exerted via eEF2K, S595 phosphorylation may globally couple the cell cycle machinery to regulatory pathways that impact eEF2K activity. ..
  2. McLeod L, Proud C. ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling. FEBS Lett. 2002;531:448-52 pubmed
    ..Only at later times is an effect on mTOR signalling observed. These data suggest that energy depletion leads to inhibition of protein synthesis through phosphorylation of eEF2 independently of inhibition of mTOR signalling. ..
  3. Stiller J, Riley J, Hall B. Are red algae plants? A critical evaluation of three key molecular data sets. J Mol Evol. 2001;52:527-39 pubmed
  4. Liu S, Leppla S. Retroviral insertional mutagenesis identifies a small protein required for synthesis of diphthamide, the target of bacterial ADP-ribosylating toxins. Mol Cell. 2003;12:603-13 pubmed
    ..KTI11, the analog of DESR1 in yeast, which was originally identified as a gene regulating the sensitivity of yeast to zymocin, is also required for diphthamide biosynthesis, implicating DESR1/KTI11 in multiple biological processes. ..
  5. Foley B, Moehring J, Moehring T. Mutations in the elongation factor 2 gene which confer resistance to diphtheria toxin and Pseudomonas exotoxin A. Genetic and biochemical analyses. J Biol Chem. 1995;270:23218-25 pubmed
    ..Western blot analysis showed that equal amounts of EF-2 were present in each of the cell strains, indicating that the mutations impaired the catalytic function of EF-2...
  6. Jørgensen R, Ortiz P, Carr Schmid A, Nissen P, Kinzy T, Andersen G. Two crystal structures demonstrate large conformational changes in the eukaryotic ribosomal translocase. Nat Struct Biol. 2003;10:379-85 pubmed
    ..The two structures also emphasize the dynamic nature of the ribosomal translocase. ..
  7. Taylor D, Nilsson J, Merrill A, Andersen G, Nissen P, Frank J. Structures of modified eEF2 80S ribosome complexes reveal the role of GTP hydrolysis in translocation. EMBO J. 2007;26:2421-31 pubmed publisher
    ..GTP hydrolysis then uncouples the mRNA-tRNA complex from the decoding center so translocation of the mRNA-tRNA moiety may be completed by a head rotation of the small subunit...
  8. Dominguez J, Gómez Lorenzo M, Martin J. Sordarin inhibits fungal protein synthesis by blocking translocation differently to fusidic acid. J Biol Chem. 1999;274:22423-7 pubmed
    ..In agreement with this conclusion, sordarin prevented the formation of peptidyl-[(3)H]puromycin on polysomes from Candida albicans. ..
  9. Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, et al. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol. 2005;25:9554-75 pubmed

More Information

Publications62

  1. Spahn C, Gomez Lorenzo M, Grassucci R, Jørgensen R, Andersen G, Beckmann R, et al. Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation. EMBO J. 2004;23:1008-19 pubmed
    ..A model is suggested, according to which the RSR is part of a mechanism for moving the tRNAs during the translocation reaction. ..
  2. Redpath N, Price N, Severinov K, Proud C. Regulation of elongation factor-2 by multisite phosphorylation. Eur J Biochem. 1993;213:689-99 pubmed
    ..These findings are discussed in terms of current knowledge of the specificity of these two protein phosphatases. ..
  3. Jørgensen R, Yates S, Teal D, Nilsson J, Prentice G, Merrill A, et al. Crystal structure of ADP-ribosylated ribosomal translocase from Saccharomyces cerevisiae. J Biol Chem. 2004;279:45919-25 pubmed
    ..These results provide insight to the inhibitory mechanism and suggest that inhibition may be caused by erroneous interaction of the translation factor with the codon-anticodon area in the P-site of the ribosome. ..
  4. Søe R, Mosley R, Justice M, Nielsen Kahn J, Shastry M, Merrill A, et al. Sordarin derivatives induce a novel conformation of the yeast ribosome translocation factor eEF2. J Biol Chem. 2007;282:657-66 pubmed
  5. Gupta P, Liu S, Batavia M, Leppla S. The diphthamide modification on elongation factor-2 renders mammalian cells resistant to ricin. Cell Microbiol. 2008;10:1687-94 pubmed publisher
    ..These data show that the presence of diphthamide in eEF-2 provides protection against ricin and suggest the hypothesis that diphthamide may have evolved to provide protection against RIPs. ..
  6. Nygard O, Nilsson L. Kinetic determination of the effects of ADP-ribosylation on the interaction of eukaryotic elongation factor 2 with ribosomes. J Biol Chem. 1990;265:6030-4 pubmed
    ..We conclude that the ADP-ribosylation affects both the association of the modified factor with pretranslocation ribosomes and the hydrolytic capacity of the factor. ..
  7. Bektaş M, Nurten R, Ergen K, Bermek E. Endogenous ADP-ribosylation for eukaryotic elongation factor 2: evidence of two different sites and reactions. Cell Biochem Funct. 2006;24:369-80 pubmed
    ..The respective sites involved in these reactions are distinct from one another as well as from diphthamide, the site of attack by diphtheria toxin. ..
  8. J rgensen R, Merrill A, Yates S, Marquez V, Schwan A, Boesen T, et al. Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry. Nature. 2005;436:979-84 pubmed publisher
    ..Notably, the toxin-bound betaTAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA...
  9. Romero Ruiz A, Bautista L, Navarro V, Heras Garvín A, March Diaz R, Castellano A, et al. Prolyl hydroxylase-dependent modulation of eukaryotic elongation factor 2 activity and protein translation under acute hypoxia. J Biol Chem. 2012;287:9651-8 pubmed publisher
    ..They unravel a novel pathway for cell adaptation to hypoxia that could have pathophysiologic relevance in tissue ischemia and cancer. ..
  10. Meskauskas A, Dinman J. Ribosomal protein L3 functions as a 'rocker switch' to aid in coordinating of large subunit-associated functions in eukaryotes and Archaea. Nucleic Acids Res. 2008;36:6175-86 pubmed publisher
    ..A model is presented describing how all three domains of L3 may function together as a 'rocker switch' to coordinate the stepwise processes of translation elongation. ..
  11. Ortiz P, Ulloque R, Kihara G, Zheng H, Kinzy T. Translation elongation factor 2 anticodon mimicry domain mutants affect fidelity and diphtheria toxin resistance. J Biol Chem. 2006;281:32639-48 pubmed
  12. Tang S, He W, Xu H, Liu W, Ruan K. Eukaryotic elongation factor 2 can bind to the synthetic oligoribonucleotide that mimics sarcin/ricin domain of rat 28S ribosomal RNA. Mol Cell Biochem. 2001;223:117-21 pubmed
    ..These results indicate that eEF2 is likely to bind directly to the sarcin/ricin domain of 28S ribosomal RNA in the process of protein synthesis. ..
  13. Smith E, Proud C. cdc2-cyclin B regulates eEF2 kinase activity in a cell cycle- and amino acid-dependent manner. EMBO J. 2008;27:1005-16 pubmed publisher
    ..These data closely match the control of Ser359 phosphorylation and indicate that cdc2 may be regulated by mTORC1. ..
  14. Liu L, Cash T, Jones R, Keith B, Thompson C, Simon M. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006;21:521-31 pubmed
    ..Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions. ..
  15. Horman S, Browne G, Krause U, Patel J, Vertommen D, Bertrand L, et al. Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr Biol. 2002;12:1419-23 pubmed
    ..Therefore, the activation of eEF2 kinase by AMPK, resulting in the phosphorylation and inactivation of eEF2, provides a novel mechanism for the inhibition of protein synthesis. ..
  16. Wilson G, Layman D, Moulton C, Norton L, Anthony T, Proud C, et al. Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats. Am J Physiol Endocrinol Metab. 2011;301:E1236-42 pubmed publisher
    ..Administering Leu or CHO supplements ?2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS. ..
  17. Browne G, Proud C. Regulation of peptide-chain elongation in mammalian cells. Eur J Biochem. 2002;269:5360-8 pubmed
    ..Conversely, eEF2 is inactivated by phosphorylation in response to stimuli that increase energy demand or reduce its supply. This likely serves to slow down protein synthesis and thus conserve energy under such circumstances. ..
  18. Redpath N, Price N, Proud C. Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase. J Biol Chem. 1996;271:17547-54 pubmed
    ..Northern blot analysis demonstrated that eEF-2K mRNA is expressed in a number of different tissues and that it may exist in multiple forms. ..
  19. Gonzalo P, Sontag B, Lavergne J, Jault J, Reboud J. Evidence for a second nucleotide binding site in rat elongation factor eEF-2 specific for adenylic nucleotides. Biochemistry. 2000;39:13558-64 pubmed
    ..Our results raise the possibility that a site specific for adenylic nucleotides and located in this insert has appeared in the course of evolution although its physiological function is still unknown. ..
  20. Ergen K, Bektaş M, Gokce S, Nurten R. Endogenous ADP-ribosylation of eukaryotic elongation factor 2 and its 32 kDa tryptic fragment. Biocell. 2007;31:61-6 pubmed
    ..These results suggest that endogenous ADP-ribosylation of 32F might be related to protein synthesis. This modification appears to be important for the cell function. ..
  21. Jørgensen R, Merrill A, Andersen G. The life and death of translation elongation factor 2. Biochem Soc Trans. 2006;34:1-6 pubmed
  22. Ortiz P, Kinzy T. Dominant-negative mutant phenotypes and the regulation of translation elongation factor 2 levels in yeast. Nucleic Acids Res. 2005;33:5740-8 pubmed
    ..The observed regulation suggests that the cell needs an optimum amount of active eEF2 to grow properly. This provides information about a new mechanism by which translation is efficiently maintained. ..
  23. Patel J, McLeod L, Vries R, Flynn A, Wang X, Proud C. Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors. Eur J Biochem. 2002;269:3076-85 pubmed
    ..Our data reveal that these stress-inducing agents, which are widely used to study stress-signalling in mammalian cells, exert multiple and complex inhibitory effects on the translational machinery. ..
  24. Nygard O, Nilsson L. Characterization of the ribosomal properties required for formation of a GTPase active complex with the eukaryotic elongation factor 2. Eur J Biochem. 1989;179:603-8 pubmed
    ..The structural alteration was accompanied by a dramatic increase in the EF-2-dependent GTPase activity. Surprisingly, ricin had no effect on the factor-catalyzed GTP hydrolysis in the presence of 60S subunits alone. ..
  25. Raimo G, Masullo M, Bocchini V. Studies on the polypeptide elongation factor 2 from Sulfolobus solfataricus. Interaction with guanosine nucleotides and GTPase activity stimulated by ribosomes. J Biol Chem. 1995;270:21082-5 pubmed
    ..The ADP-ribosylation of SsEF-2 does not significantly affect either the binding of GDP and GTP or the kinetics of the GTPaser. A hypothesis on the stimulation by ribosome of SsEF-2 GTPase is proposed. ..
  26. Moreira D, Le Guyader H, Philippe H. The origin of red algae and the evolution of chloroplasts. Nature. 2000;405:69-72 pubmed
    ..Thus, our study provides evidence from nuclear markers for a single primary endosymbiosis at the origin of these groups, and supports a kingdom Plantae comprising green plants, red algae and glaucophytes. ..
  27. Jørgensen R, Carr Schmid A, Ortiz P, Kinzy T, Andersen G. Purification and crystallization of the yeast elongation factor eEF2. Acta Crystallogr D Biol Crystallogr. 2002;58:712-5 pubmed
    ..A yeast strain expressing a functional histidine-tagged eEF2 as the only form of the protein further allows facilitated purification of the factor for both structural and functional studies. ..
  28. Perentesis J, Phan L, Gleason W, LaPorte D, Livingston D, Bodley J. Saccharomyces cerevisiae elongation factor 2. Genetic cloning, characterization of expression, and G-domain modeling. J Biol Chem. 1992;267:1190-7 pubmed
    ..Based upon these observations, we have modeled the G-domain of the deduced EF-2 protein sequence to the solved crystallographic structure for EF-Tu. ..
  29. Connolly E, Braunstein S, Formenti S, Schneider R. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol. 2006;26:3955-65 pubmed
    ..Breast cancer cells therefore acquire resistance to hypoxia by uncoupling oxygen-responsive signaling pathways from mTOR function, eliminating inhibition of protein synthesis mediated by 4E-BP1 and eEF2. ..
  30. Py B, Boyce M, Yuan J. A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses. Autophagy. 2009;5:393-6 pubmed
  31. Liu S, Milne G, Kuremsky J, Fink G, Leppla S. Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2. Mol Cell Biol. 2004;24:9487-97 pubmed
    ..The physiological function of diphthamide and the basis of its ubiquity remain a mystery, but evidence is presented that Dph1 to -3 function in vivo as a protein complex in multiple cellular processes. ..
  32. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo A, Kool M, et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell. 2013;153:1064-79 pubmed publisher
    ..Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. PAPERCLIP: ..
  33. González Terán B, Cortes J, Manieri E, Matesanz N, Verdugo Á, Rodriguez M, et al. Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis. J Clin Invest. 2013;123:164-78 pubmed publisher
    ..These results identify a new signaling pathway that regulates TNF-? production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-? production is involved. ..
  34. Thomas T, Kumar N, Cavicchioli R. Effects of ribosomes and intracellular solutes on activities and stabilities of elongation factor 2 proteins from psychrotolerant and thermophilic methanogens. J Bacteriol. 2001;183:1974-82 pubmed
    ..These findings illustrate the different physiological strategies that have evolved in two phylogenetically related but thermally distinct methanogens to enable EF-2 to function satisfactorily...
  35. Greganova E, Altmann M, Bütikofer P. Unique modifications of translation elongation factors. FEBS J. 2011;278:2613-24 pubmed publisher
    ..We review the biosynthesis, attachment and physiological roles of these unique protein modifications and discuss common and separate features of the target proteins, which represent essential proteins in all organisms. ..
  36. Mohammadi P, Moieni A, Komatsu S. Comparative proteome analysis of drought-sensitive and drought-tolerant rapeseed roots and their hybrid F1 line under drought stress. Amino Acids. 2012;43:2137-52 pubmed publisher
  37. Cursino L, Lima N, Murillo R, Nuñez C, Merfort I, Humar M. Isolation of Flavonoids from Deguelia duckeana and Their Effect on Cellular Viability, AMPK, eEF2, eIF2 and eIF4E. Molecules. 2016;21: pubmed publisher
    ..The initiation factor eIF2alpha was not affected. Further studies are needed to elucidate the importance of the observed effects on protein synthesis and potential therapeutic perspectives. ..
  38. Kageyama T, Ohishi M, Miyamoto S, Mizushima H, Iwamoto R, Mekada E. Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity. J Biochem. 2007;142:95-104 pubmed
    ..The anti-DT monoclonal antibody administered with CRM197 reduced the anti- tumourigenic effect of CRM197, indicating that the toxicity of CRM197 potentiates its anti- tumourigenic effect. ..
  39. Brinkmann U, Brinkmann E, Gallo M, Scherf U, Pastan I. Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry. 1996;35:6891-9 pubmed
    ..The observation that CAS antisense can interfere with apoptosis mediated by TNF and ADP-ribosylating toxins suggests that CAS may play a role in selected pathways of apoptosis. ..
  40. Ogasawara T, Ito K, Igarashi K, Yutsudo T, Nakabayashi N, Takeda Y. Inhibition of protein synthesis by a Vero toxin (VT2 or Shiga-like toxin II) produced by Escherichia coli O157:H7 at the level of elongation factor 1-dependent aminoacyl-tRNA binding to ribosomes. Microb Pathog. 1988;4:127-35 pubmed
    ..VT2 did not affect Met-tRNAf binding to ribosomes, non-enzymatic binding of aminoacyl-tRNA to ribosomes, peptide bond formation or translocation. ..
  41. Christophersen C, Karlsen J, Nielsen M, Riis B. Eukaryotic elongation factor-2 (eEF-2) activity in bovine mammary tissue in relation to milk protein synthesis. J Dairy Res. 2002;69:205-12 pubmed
    ..This strongly suggests that eEF-2 may be a limiting factor in milk protein synthesis. ..
  42. Sengupta J, Nilsson J, Gursky R, Kjeldgaard M, Nissen P, Frank J. Visualization of the eEF2-80S ribosome transition-state complex by cryo-electron microscopy. J Mol Biol. 2008;382:179-87 pubmed publisher
    ..This complex is structurally distinct from the eEF2-bound 80S ribosome complexes previously reported, and analysis of this map sheds light on the GTPase-coupled translocation mechanism. ..
  43. Fiala I, Bartošová P. History of myxozoan character evolution on the basis of rDNA and EF-2 data. BMC Evol Biol. 2010;10:228 pubmed publisher
  44. Connell S, Trieber C, Dinos G, Einfeldt E, Taylor D, Nierhaus K. Mechanism of Tet(O)-mediated tetracycline resistance. EMBO J. 2003;22:945-53 pubmed
  45. Kamaishi T, Hashimoto T, Nakamura Y, Masuda Y, Nakamura F, Okamoto K, et al. Complete nucleotide sequences of the genes encoding translation elongation factors 1 alpha and 2 from a microsporidian parasite, Glugea plecoglossi: implications for the deepest branching of eukaryotes. J Biochem. 1996;120:1095-103 pubmed
    ..If the phylogenetic relationship inferred from the present analysis are correct, microsporidians might be extremely ancient eukaryotes that diverged before the occurrence of mitochondrial symbiosis. ..
  46. Eckertova M, Ondrejcakova M, Krskova K, Zorad S, Jezova D. Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis. Br J Pharmacol. 2011;162:452-63 pubmed publisher
    ..These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism. ..
  47. Wang S, Zheng Y, Yan J, Zhu Z, Wu Z, Ding Y. Alpha-momorcharin: a ribosome-inactivating protein from Momordica charantia, possessing DNA cleavage properties. Protein Pept Lett. 2013;20:1257-63 pubmed
    ..These results may also assist in the characterization and elucidation of the DNase-like enzymatic properties of other RIPs. ..
  48. Belelovsky K, Elkobi A, Kaphzan H, Nairn A, Rosenblum K. A molecular switch for translational control in taste memory consolidation. Eur J Neurosci. 2005;22:2560-8 pubmed
  49. Raimo G, Masullo M, Scarano G, Bocchini V. The site for GTP hydrolysis on the archaeal elongation factor 2 is unmasked by aliphatic alcohols. Biochimie. 1996;78:832-7 pubmed
    ..The stimulatory effect of ethylene glycol/Ba2+ was attributed to the increased affinity for GTP, probably related to a conformational change occurring in a hydrophobic region near the catalytic site. ..
  50. Wei H, Xiang L, Wayne A, Chertov O, FitzGerald D, Bera T, et al. Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy. Proc Natl Acad Sci U S A. 2012;109:6898-903 pubmed publisher
    ..Incubation of sensitive cells with the methylation inhibitor 5-azacytidine prevented the emergence of resistant cells, suggesting that this agent in combination with HA22 may be useful in the treatment of some cases of ALL. ..
  51. Li X, Alafuzoff I, Soininen H, Winblad B, Pei J. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 2005;272:4211-20 pubmed
  52. Hu X, Zuckerman K. Cell cycle and transcriptional control of human myeloid leukemic cells by transforming growth factor beta. Leuk Lymphoma. 2000;38:235-46 pubmed
    ..In summary, TGFbeta1 inhibits growth of human myeloid leukemic cells through multiple pathways, whereas the "cdk inhibitor" p27 is both a positive and negative regulator. ..
  53. Fritzen A, Frøsig C, Jeppesen J, Jensen T, Lundsgaard A, Serup A, et al. Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. Cell Signal. 2016;28:663-74 pubmed publisher
    ..Furthermore, LC3 lipidation is increased in muscle lacking functional AMPKα2 during fasting and aging. Moreover, LC3 lipidation seems not to be a universal response to muscle contraction in mice. ..