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- Title
Bypassing a kinase activity with an ATP-competitive drug.
- Authors
Papa, Feroz R; Zhang, Chao; Shokat, Kevan; Walter, Peter
- 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 RNA to 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.
- Publication
Science (New York, N.Y.), 2003, Vol 302, Issue 5650, p1533
- ISSN
1095-9203
- Publication type
Journal Article
- DOI
10.1126/science.1090031