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dc.contributor.authorHodgson, George
dc.contributor.authorAndreeva, Antonina
dc.contributor.authorBertolotti, Anne
dc.date.accessioned2022-01-04T14:32:09Z
dc.date.available2022-01-04T14:32:09Z
dc.date.issued2021-12
dc.date.submitted2021-07-13
dc.identifier.issn2046-2441
dc.identifier.otherrsob210205
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331893
dc.description.abstractPhosphorylation of the translation initiation factor eIF2α is a rapid and vital cellular defence against many forms of stress. In mammals, the levels of eIF2α phosphorylation are set through the antagonistic action of four protein kinases and two heterodimeric protein phosphatases. The phosphatases are composed of the catalytic subunit PP1 and one of two related non-catalytic subunits, PPP1R15A or PPP1R15B (R15A or R15B). Here, we generated a series of R15 truncation mutants and tested their properties in mammalian cells. We show that substrate recruitment is encoded by an evolutionary conserved region in R15s, R15A325-554 and R15B340-639. G-actin, which has been proposed to confer selectivity to R15 phosphatases, does not bind these regions, indicating that it is not required for substrate binding. Fragments containing the substrate-binding regions but lacking the PP1-binding motif trapped the phospho-substrate and caused accumulation of phosphorylated eIF2α in unstressed cells. Activity assays in cells showed that R15A325-674 and R15B340-713, encompassing the substrate-binding region and the PP1-binding region, exhibit wild-type activity. This work identifies the substrate-binding region in R15s, that functions as a phospho-substrate trapping mutant, thereby defining a key region of R15s for follow up studies.
dc.languageen
dc.publisherThe Royal Society
dc.subjectShort communications
dc.subjectphosphatase
dc.subjectPP1
dc.subjectPPP1R15
dc.subjectintegrated stress response
dc.subjecteIF2α phosphorylation
dc.titleSubstrate recognition determinants of human eIF2α phosphatases.
dc.typeArticle
dc.date.updated2022-01-04T14:32:08Z
prism.issueIdentifier12
prism.publicationNameOpen Biol
prism.volume11
dc.identifier.doi10.17863/CAM.79343
dcterms.dateAccepted2021-10-21
rioxxterms.versionofrecord10.1098/rsob.210205
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHodgson, George [0000-0002-8905-734X]
dc.contributor.orcidAndreeva, Antonina [0000-0002-0450-0091]
dc.contributor.orcidBertolotti, Anne [0000-0002-9185-0558]
dc.identifier.eissn2046-2441
pubs.funder-project-idWellcome Trust Principal Investigator Award (206367/Z/ 17/Z)
pubs.funder-project-idMedical Research Council (MC_U105185860)
cam.issuedOnline2021-12


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