Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic
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Fecha
2015-05
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Facultad/escuela
Idioma
en
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Editor
ELIFE SCIENCES PUBLICATIONS
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Licencia CC
Licencia CC
Resumen
Two 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.
Notas
Indexación: Web of Science
Palabras clave
MULTIPLE-MYELOMA, MESSENGER-RNA, MAPK PATHWAY, IRE1, INHIBITORS, RAF, MECHANISM, CELLS, TRANSLATION, SIGNALS
Citación
eLife 2015;4:e05434