4xpn
Crystal Structure of Protein Phosphate 1 complexed with PP1 binding domain of GADD34
Structural highlights
FunctionPR15A_HUMAN Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe attenuation of protein synthesis via the phosphorylation of eIF2alpha 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 eIF2alpha phosphatase complex that returns mammalian cells to normal protein synthesis following stress. The molecular basis by which GADD34 recruits PP1 and its substrate eIF2alpha are not fully understood, hindering our understanding of the remarkable selectivity of the GADD34:PP1 phosphatase for eIF2alpha. Here, we report detailed structural and functional analyses of the GADD34:PP1 holoenzyme and its recruitment of eIF2alpha. The data highlight independent interactions of PP1 and eIF2alpha 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 eIF2alpha phosphatase and establishes the foundation for future translational work. Structural and Functional Analysis of the GADD34:PP1 eIF2alpha Phosphatase.,Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, Peti W Cell Rep. 2015 Jun 30;11(12):1885-91. doi: 10.1016/j.celrep.2015.05.043. Epub, 2015 Jun 18. PMID:26095357[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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