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eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.

Kenner LR, Anand AA, Nguyen HC, Myasnikov AG, Klose CJ, McGeever LA, Tsai JC, Miller-Vedam LE, Walter P, Frost A
Science 364 491-495 (2019)
Related entries: 6o81, 6o85

Cited: 55 times
EuropePMC logo PMID: 31048491

Abstract

The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.

Reviews - 6o9z mentioned but not cited (2)

  1. Move and countermove: the integrated stress response in picorna- and coronavirus-infected cells. Aloise C, Schipper JG, de Groot RJ, van Kuppeveld FJ. Curr Opin Immunol 79 102254 (2022)
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Articles - 6o9z mentioned but not cited (8)

  1. eIF2B conformation and assembly state regulate the integrated stress response. Schoof M, Boone M, Wang L, Lawrence R, Frost A, Walter P. Elife 10 e65703 (2021)
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  5. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Kenner LR, Anand AA, Nguyen HC, Myasnikov AG, Klose CJ, McGeever LA, Tsai JC, Miller-Vedam LE, Walter P, Frost A. Science 364 491-495 (2019)
  6. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. Mol Cell 81 88-103.e6 (2021)
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Reviews citing this publication (18)

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Articles citing this publication (27)

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  3. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease. Oliveira MM, Lourenco MV, Longo F, Kasica NP, Yang W, Ureta G, Ferreira DDP, Mendonça PHJ, Bernales S, Ma T, De Felice FG, Klann E, Ferreira ST. Sci Signal 14 eabc5429 (2021)
  4. A structural biology community assessment of AlphaFold2 applications. Akdel M, Pires DEV, Pardo EP, Jänes J, Zalevsky AO, Mészáros B, Bryant P, Good LL, Laskowski RA, Pozzati G, Shenoy A, Zhu W, Kundrotas P, Serra VR, Rodrigues CHM, Dunham AS, Burke D, Borkakoti N, Velankar S, Frost A, Basquin J, Lindorff-Larsen K, Bateman A, Kajava AV, Valencia A, Ovchinnikov S, Durairaj J, Ascher DB, Thornton JM, Davey NE, Stein A, Elofsson A, Croll TI, Beltrao P. Nat Struct Mol Biol 29 1056-1067 (2022)
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  6. Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells. Della-Flora Nunes G, Wilson ER, Marziali LN, Hurley E, Silvestri N, He B, O'Malley BW, Beirowski B, Poitelon Y, Wrabetz L, Feltri ML. Nat Commun 12 3285 (2021)
  7. A complex IRES at the 5'-UTR of a viral mRNA assembles a functional 48S complex via an uAUG intermediate. Neupane R, Pisareva VP, Rodriguez CF, Pisarev AV, Fernández IS. Elife 9 (2020)
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  9. Molecular architecture of 40S translation initiation complexes on the hepatitis C virus IRES. Brown ZP, Abaeva IS, De S, Hellen CUT, Pestova TV, Frank J. EMBO J 41 e110581 (2022)
  10. Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts. Bochler A, Querido JB, Prilepskaja T, Soufari H, Simonetti A, Del Cistia ML, Kuhn L, Ribeiro AR, Valášek LS, Hashem Y. Cell Rep 33 108534 (2020)
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  12. A structural inventory of native ribosomal ABCE1-43S pre-initiation complexes. Kratzat H, Mackens-Kiani T, Ameismeier M, Potocnjak M, Cheng J, Dacheux E, Namane A, Berninghausen O, Herzog F, Fromont-Racine M, Becker T, Beckmann R. EMBO J 40 e105179 (2021)
  13. C9orf72 regulates the unfolded protein response and stress granule formation by interacting with eIF2α. Zheng W, Wang K, Wu Y, Yan G, Zhang C, Li Z, Wang L, Chen S. Theranostics 12 7289-7306 (2022)
  14. Large-scale movement of eIF3 domains during translation initiation modulate start codon selection. Llácer JL, Hussain T, Dong J, Villamayor L, Gordiyenko Y, Hinnebusch AG. Nucleic Acids Res 49 11491-11511 (2021)
  15. Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease. Norris K, Hodgson RE, Dornelles T, Allen KE, Abell BM, Ashe MP, Campbell SG. J Biol Chem 296 100207 (2021)
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  17. A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Schmidt S, Gay D, Uthe FW, Denk S, Paauwe M, Matthes N, Diefenbacher ME, Bryson S, Warrander FC, Erhard F, Ade CP, Baluapuri A, Walz S, Jackstadt R, Ford C, Vlachogiannis G, Valeri N, Otto C, Schülein-Völk C, Maurus K, Schmitz W, Knight JRP, Wolf E, Strathdee D, Schulze A, Germer CT, Rosenwald A, Sansom OJ, Eilers M, Wiegering A. Nat. Cell Biol. 21 1413-1424 (2019)
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  19. Dysregulation of Stress-Induced Translational Control by Porphyromonas gingivalis in Host Cells. Knowles AA, Campbell SG, Cross NA, Stafford P. Microorganisms 11 606 (2023)
  20. Fluorescence Intensity-Based eIF2B's Guanine Nucleotide-Exchange Factor Activity Assay. Sekine Y, Ron D, Zyryanova AF. Methods Mol Biol 2428 187-196 (2022)
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  22. PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy. Zhao N, Li N, Wang T. J Cell Biol 222 e202208147 (2023)
  23. SARS-CoV-2 variant-specific differences in inhibiting the effects of the PKR-activated integrated stress response. Christ W, Klingström J, Tynell J. Virus Res 339 199271 (2024)
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  26. eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition. Wuerth JD, Habjan M, Kainulainen M, Berisha B, Bertheloot D, Superti-Furga G, Pichlmair A, Weber F. mBio 11 (2020)
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