Abstract

Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylation of the bifunctional transmembrane kinase Ire1, which induces its endoribonuclease activity. The endoribonuclease initiates nonconventional splicing of HAC1 messenger RNAto trigger the unfolded-protein response (UPR). We explored the role of Ire1's kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized Ire1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.

Keywords

AutophosphorylationEndoribonucleaseUnfolded protein responseEndoplasmic reticulumProtein kinase domainKinaseCell biologyPhosphorylationChemistryProtein kinase ARNA splicingBiologyBiochemistryMutantRNARNase PGene

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Publication Info

Year
2003
Type
article
Volume
302
Issue
5650
Pages
1533-1537
Citations
227
Access
Closed

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Cite This

Feroz R. Papa, Chao Zhang, Kevan M. Shokat et al. (2003). Bypassing a Kinase Activity with an ATP-Competitive Drug. Science , 302 (5650) , 1533-1537. https://doi.org/10.1126/science.1090031

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DOI
10.1126/science.1090031