4ut2

X-ray structure of the human PP1 gamma catalytic subunit treated with ascorbate

spinqualitylabelsall models 4ut2, resolution 1.96Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ut2 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MN, PO4 NonStd Res: CSO Related: 4ut3 Activity: Phosphoprotein phosphatase, with EC number 3.1.3.16 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PP1G_HUMAN] Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Publication Abstract from PubMed Phosphorylation of translation initiation factor 2alpha (eIF2alpha) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2alpha phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2alpha phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4-regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia-reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4-GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2alpha phosphorylation to protect tissues under stress. Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha-mediated stress signaling.,Santos CX, Hafstad AD, Beretta M, Zhang M, Molenaar C, Kopec J, Fotinou D, Murray TV, Cobb AM, Martin D, Zeh Silva M, Anilkumar N, Schroder K, Shanahan CM, Brewer AC, Brandes RP, Blanc E, Parsons M, Belousov V, Cammack R, Hider RC, Steiner RA, Shah AM EMBO J. 2016 Feb 1;35(3):319-34. doi: 10.15252/embj.201592394. Epub 2016 Jan 7. PMID:26742780 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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