Show simple item record

dc.contributor.authorCrespillo-Casado, Ana
dc.contributor.authorClaes, Zander
dc.contributor.authorChoy, Meng S.
dc.contributor.authorPeti, Wolfgang
dc.contributor.authorBollen, Mathieu
dc.contributor.authorRon, David
dc.date.accessioned2018-09-04T17:16:12Z
dc.date.available2018-09-04T17:16:12Z
dc.date.issued2018-05-18
dc.identifier.citationCrespillo-Casado, A., Claes, Z., Choy, M. S., Peti, W., Bollen, M., & Ron, D. (2018). A Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2α. J. Biol. Chem. 2018 293: 7766-. doi:10.1074/jbc.RA118.002325en_US
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.pmid29618508
dc.identifier.doi10.1074/jbc.RA118.002325
dc.identifier.urihttp://hdl.handle.net/10150/628639
dc.description.abstractThe integrated stress response (ISR) is regulated by kinases that phosphorylate the subunit of translation initiation factor 2 and phosphatases that dephosphorylate it. Genetic and biochemical observations indicate that the eIF2(P)-directed holophosphatase, a therapeutic target in diseases of protein misfolding, is comprised of a regulatory subunit, PPP1R15, and a catalytic subunit, protein phosphatase 1 (PP1). In mammals, there are two isoforms of the regulatory subunit, PPP1R15A and PPP1R15B, with overlapping roles in the essential function of eIF2(P) dephosphorylation. However, conflicting reports have appeared regarding the requirement for an additional co-factor, G-actin, in enabling substrate-specific dephosphorylation by PPP1R15-containing PP1 holoenzymes. An additional concern relates to the sensitivity of the holoenzyme to the [(o-chlorobenzylidene)amino]guanidines Sephin1 or guanabenz, putative small-molecule proteostasis modulators. It has been suggested that the source and method of purification of the PP1 catalytic subunit and the presence or absence of an N-terminal repeat-containing region in the PPP1R15A regulatory subunit might influence the requirement for G-actin and sensitivity of the holoenzyme to inhibitors. We found that eIF2(P) dephosphorylation by PP1 was moderately stimulated by repeat-containing PPP1R15A in an unphysiological low ionic strength buffer, whereas stimulation imparted by the co-presence of PPP1R15A and G-actin was observed under a broad range of conditions, low and physiological ionic strength, regardless of whether the PPP1R15A regulatory subunit had or lacked the N-terminal repeat-containing region and whether it was paired with native PP1 purified from rabbit muscle or recombinant PP1 purified from bacteria. Furthermore, none of the PPP1R15A-containing holophosphatases tested were inhibited by Sephin1 or guanabenz.en_US
dc.description.sponsorshipWellcome Trust principal research fellowship [Wellcome 200848/Z/16/Z]; Wellcome Trust strategic award [Wellcome 100140]; National Institute of Health [R01NS091336]; American Diabetes Association Pathway to Stop Diabetes [1-14-ACN-31]; Flemish Concerted Research Action [GOA15/016]en_US
dc.language.isoenen_US
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCen_US
dc.relation.urlhttp://www.jbc.org/lookup/doi/10.1074/jbc.RA118.002325en_US
dc.rights© 2018 Crespillo-Casado et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.en_US
dc.subjectphosphoprotein phosphatase 1 (PP1)en_US
dc.subjecteukaryotic initiation factor 2 (eIF2)en_US
dc.subjectenzyme inhibitoren_US
dc.subjectG-actinen_US
dc.subjectproteostasisen_US
dc.subjectguanabenzen_US
dc.subjectintegrated stress responseen_US
dc.subjectprotein synthesisen_US
dc.subjectSephin1en_US
dc.titleA Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2αen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Chem & Biochemen_US
dc.identifier.journalJOURNAL OF BIOLOGICAL CHEMISTRYen_US
dc.description.note12 month embargo; published online: 4 April 2018en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleJournal of Biological Chemistry
dc.source.volume293
dc.source.issue20
dc.source.beginpage7766
dc.source.endpage7776


Files in this item

Thumbnail
Name:
J._Biol._Chem.-2018-Crespillo- ...
Size:
2.277Mb
Format:
PDF
Description:
Final Published version

This item appears in the following Collection(s)

Show simple item record