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Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase.

Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, Peti W
Cell Rep 11 1885-91 (2015)
Cited: 81 times
EuropePMC logo PMID: 26095357

Abstract

The attenuation of protein synthesis via the phosphorylation of eIF2α is a major stress response of all eukaryotic cells. The growth-arrest- and DNA-damage-induced transcript 34 (GADD34) bound to the serine/threonine protein phosphatase 1 (PP1) is the necessary eIF2α phosphatase complex that returns mammalian cells to normal protein synthesis following stress. The molecular basis by which GADD34 recruits PP1 and its substrate eIF2α are not fully understood, hindering our understanding of the remarkable selectivity of the GADD34:PP1 phosphatase for eIF2α. Here, we report detailed structural and functional analyses of the GADD34:PP1 holoenzyme and its recruitment of eIF2α. The data highlight independent interactions of PP1 and eIF2α with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. This work greatly enhances our molecular understanding of a major cellular eIF2α phosphatase and establishes the foundation for future translational work.

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  2. Pneumoviral Phosphoprotein, a Multidomain Adaptor-Like Protein of Apparent Low Structural Complexity and High Conformational Versatility. Cardone C, Caseau CM, Pereira N, Sizun C. Int J Mol Sci 22 1537 (2021)

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  1. The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism. Kumar GS, Gokhan E, De Munter S, Bollen M, Vagnarelli P, Peti W, Page R. Elife 5 e16539 (2016)
  2. Molecular Insights into the Fungus-Specific Serine/Threonine Protein Phosphatase Z1 in Candida albicans. Chen E, Choy MS, Petrényi K, Kónya Z, Erdődi F, Dombrádi V, Peti W, Page R. mBio 7 e00872-16 (2016)
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  4. PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107. Fowle H, Zhao Z, Xu Q, Wasserman JS, Wang X, Adeyemi M, Feiser F, Kurimchak AN, Atar D, McEwan BC, Kettenbach AN, Page R, Peti W, Dunbrack RL, Graña X. Elife 10 e63181 (2021)
  5. Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. Bonsor DA, Alexander P, Snead K, Hartig N, Drew M, Messing S, Finci LI, Nissley DV, McCormick F, Esposito D, Rodriguez-Viciana P, Stephen AG, Simanshu DK. Nat Struct Mol Biol 29 966-977 (2022)
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Reviews citing this publication (21)

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  19. Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment. Van Stiphout CM, Luu AK, Viloria-Petit AM. Cancers (Basel) 14 4544 (2022)
  20. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review. De Masi R, Orlando S. Int J Mol Sci 23 7373 (2022)
  21. The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP). Hicks D, Giresh K, Wrischnik LA, Weiser DC. Int J Mol Sci 24 17321 (2023)

Articles citing this publication (51)

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  26. Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells. Wabnitz GH, Kirchgessner H, Jahraus B, Umansky L, Shenolikar S, Samstag Y. Mol Cell Biol 38 e00041-18 (2018)
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