Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic

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dc.contributor.authorMendez, Aaron S
dc.contributor.authorAlfaro, Jennifer
dc.contributor.authorMorales-Soto, Marisol A
dc.contributor.authorDar, Arvin C
dc.contributor.authorMcCullagh, Emma
dc.contributor.authorGotthardt, Katja
dc.contributor.authorLi, Han
dc.contributor.authorAcosta-Alvear, Diego
dc.contributor.authorSidrauski, Carmela
dc.contributor.authorKorennykh, Alexei V
dc.contributor.authorBernales, Sebastian
dc.contributor.authorShokat, Kevan M
dc.contributor.authorWalter, Peter
dc.date.accessioned2016-07-29T16:54:02Z
dc.date.available2016-07-29T16:54:02Z
dc.date.issued2015-05
dc.descriptionIndexación: Web of Sciencees
dc.description.abstractTwo ER membrane-resident transmembrane kinases, IRE1 and PERK, function as stress sensors in the unfolded protein response. IRE1 also has an endoribonuclease activity, which initiates a non-conventional mRNA splicing reaction, while PERK phosphorylates eIF2α. We engineered a potent small molecule, IPA, that binds to IRE1's ATP-binding pocket and predisposes the kinase domain to oligomerization, activating its RNase. IPA also inhibits PERK but, paradoxically, activates it at low concentrations, resulting in a bell-shaped activation profile. We reconstituted IPA-activation of PERK-mediated eIF2α phosphorylation from purified components. We estimate that under conditions of maximal activation less than 15% of PERK molecules in the reaction are occupied by IPA. We propose that IPA binding biases the PERK kinase towards its active conformation, which trans-activates apo-PERK molecules. The mechanism by which partial occupancy with an inhibitor can activate kinases may be wide-spread and carries major implications for design and therapeutic application of kinase inhibitors.en
dc.description.urihttps://elifesciences.org/content/4/e05434
dc.identifier.citationeLife 2015;4:e05434es
dc.identifier.issn2050-084X
dc.identifier.otherDOI: http://dx.doi.org/10.7554/eLife.05434.001
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/1570
dc.language.isoenen
dc.publisherELIFE SCIENCES PUBLICATIONSes
dc.subjectMULTIPLE-MYELOMAes
dc.subjectMESSENGER-RNAes
dc.subjectMAPK PATHWAYes
dc.subjectIRE1es
dc.subjectINHIBITORSes
dc.subjectRAFes
dc.subjectMECHANISMes
dc.subjectCELLSes
dc.subjectTRANSLATIONes
dc.subjectSIGNALSes
dc.titleEndoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimices
dc.typeArtículoes
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