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dc.contributor.authorChen, Rumingen
dc.contributor.authorRato, Cláudiaen
dc.contributor.authorYan, Yahuien
dc.contributor.authorCrespillo-Casado, Anaen
dc.contributor.authorClarke, Hanna Jen
dc.contributor.authorHarding, Heatheren
dc.contributor.authorMarciniak, Stefanen
dc.contributor.authorRead, Randyen
dc.contributor.authorRon, Daviden
dc.date.accessioned2015-05-26T11:42:14Z
dc.date.available2015-05-26T11:42:14Z
dc.date.issued2015-03-16en
dc.identifier.citationChen et al. eLife (2015) Vol. 4: e04871. DOI: 10.7554/eLife.04871en
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247968
dc.description.abstractDephosphorylation 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 eIF2a 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.
dc.description.sponsorshipWellcome Trust, MRC, EU FP7
dc.languageEnglishen
dc.language.isoenen
dc.publishereLife
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleG-actin provides substrate-specificity to eukaryotic initiation factor 2a holophosphatasesen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from eLife via http://dx.doi.org/10.7554/eLife.04871.001en
prism.numbere04871en
prism.publicationDate2015en
prism.publicationNameeLifeen
prism.volume4en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.funderEU FP7
dc.rioxxterms.projectid084812/Z/08/Z
dc.rioxxterms.projectid082961/Z/07/Z
dc.rioxxterms.projectidG1002610
dc.rioxxterms.projectid277713
dcterms.dateAccepted2015-03-12en
rioxxterms.versionofrecord10.7554/eLife.04871en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-03-16en
dc.contributor.orcidYan, Yahui [0000-0001-6934-9874]
dc.contributor.orcidHarding, Heather [0000-0002-7359-7974]
dc.contributor.orcidMarciniak, Stefan [0000-0001-8472-7183]
dc.contributor.orcidRead, Randy [0000-0001-8273-0047]
dc.contributor.orcidRon, David [0000-0002-3014-5636]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (082961/Z/07/Z)
pubs.funder-project-idWellcome Trust (084812/Z/08/Z)
pubs.funder-project-idMRC (G1002610)
pubs.funder-project-idMRC (G0601840)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idEC FP7 CP (277713)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales