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dc.contributor.authorYan, Yahui
dc.contributor.authorHarding, Heather P
dc.contributor.authorRon, David
dc.date.accessioned2021-11-10T02:09:20Z
dc.date.available2021-11-10T02:09:20Z
dc.date.issued2021-10-08
dc.identifier.issn1545-9993
dc.identifier.otherPMC8500838
dc.identifier.other34625748
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330533
dc.description.abstractMany regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c-PPP1R15A-G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1545-9985
dc.sourcenlmid: 101186374
dc.titleHigher-order phosphatase-substrate contacts terminate the integrated stress response.
dc.typeArticle
dc.date.updated2021-11-10T02:07:47Z
prism.endingPage846
prism.issueIdentifier10
prism.publicationNameNature structural & molecular biology
prism.startingPage835
prism.volume28
dc.identifier.doi10.17863/CAM.77976
rioxxterms.versionofrecord10.1038/s41594-021-00666-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidYan, Yahui [0000-0001-6934-9874]
dc.contributor.orcidHarding, Heather P [0000-0002-7359-7974]
dc.contributor.orcidRon, David [0000-0002-3014-5636]
pubs.funder-project-idWellcome Trust (200848/Z/16/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International