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Bypassing a kinase activity with an ATP-competitive drug.

Science (New York, N.Y.) | Nov 28, 2003

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.

Pubmed ID: 14564015 RIS Download

Mesh terms: Adenosine Diphosphate | Adenosine Triphosphate | Basic-Leucine Zipper Transcription Factors | Binding Sites | Binding, Competitive | Cytosol | Dithiothreitol | Endoplasmic Reticulum | Endoribonucleases | Enzyme Activation | Ligands | Membrane Glycoproteins | Models, Biological | Mutagenesis, Site-Directed | Phosphorylation | Protein Conformation | Protein Folding | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Pyrazoles | Pyrimidines | RNA Splicing | RNA, Messenger | Repressor Proteins | Saccharomyces cerevisiae Proteins | Signal Transduction | Structure-Activity Relationship | Substrate Specificity | Transcription Factors | Up-Regulation