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

Aaron S. Mendez, Jennifer Alfaro, Marisol A. Morales-Soto, Arvin C. Dar, Emma McCullagh, Katja Gotthardt, Han Li, Diego Acosta-Alvear, Carmela Sidrauski, Alexei V. Korennykh, Sebastian Bernales, Kevan M. Shokat, Peter Walter

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere05434
JournaleLife
Volume4
Issue numberMAY
DOIs
StatePublished - May 19 2015

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic'. Together they form a unique fingerprint.

  • Cite this

    Mendez, A. S., Alfaro, J., Morales-Soto, M. A., Dar, A. C., McCullagh, E., Gotthardt, K., Li, H., Acosta-Alvear, D., Sidrauski, C., Korennykh, A. V., Bernales, S., Shokat, K. M., & Walter, P. (2015). Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. eLife, 4(MAY), [e05434]. https://doi.org/10.7554/eLife.05434