Journal
ELIFE
Volume 4, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.04871
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Funding
- Wellcome Trust [084812/Z/08/Z, 082961/Z/07/Z]
- UK Medical Research Council [G1002610]
- European Commission (EU FP7) [277713]
- Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research [100140]
- MRC [G0601840, G1002610] Funding Source: UKRI
- British Lung Foundation [APHD11-4] Funding Source: researchfish
- Medical Research Council [G0601840, G1002610] Funding Source: researchfish
- Wellcome Trust [084812/Z/08/Z] Funding Source: Wellcome Trust
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Dephosphorylation of eukaryotic translation initiation factor 2a (eIF2a) restores protein synthesis at the waning of stress responses and requires a PP1 catalytic subunit and a regulatory subunit, PPP1R15A/GADD34 or PPP1R15B/CReP. Surprisingly, PPP1R15 PP1 binary complexes reconstituted in vitro lacked substrate selectivity. However, selectivity was restored by crude cell lysate or purified G-actin, which joined PPP1R15- PP1 to form a stable ternary complex. In crystal structures of the non-selective PPP1R15B-PP1G complex, the functional core of PPP1R15 made multiple surface contacts with PP1G, but at a distance from the active site, whereas in the substrate selective ternary complex, actin contributes to one face of a platform encompassing the active site. Computational docking of the N-terminal lobe of elF2a at this platform placed phosphorylated serine 51 near the active site. Mutagenesis of predicted surface-contacting residues enfeebled dephosphorylation, suggesting that avidity for the substrate plays an important role in imparting specificity on the PPP1R15B-PP1G actin ternary complex.
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