4UT2: X-ray Structure Of The Human Pp1 Gamma Catalytic Subunit Treated With Ascorbate

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.
PDB ID: 4UT2Download
MMDB ID: 131104
PDB Deposition Date: 2014/7/17
Updated in MMDB: 2015/07
Experimental Method:
x-ray diffraction
Resolution: 1.96  Å
Source Organism:
Similar Structures:
Biological Unit for 4UT2: monomeric; determined by author and by software (PISA)
Molecular Components in 4UT2
Label Count Molecule
Protein (1 molecule)
Serine/threonine-protein Phosphatase Pp1-gamma Catalytic Subunit(Gene symbol: PPP1CC)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

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