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- Title
Divergent allosteric control of the IRE1? endoribonuclease using kinase inhibitors.
- Authors
Wang, Likun; Perera, B Gayani K; Hari, Sanjay B; Bhhatarai, Barun; Backes, Bradley J; Seeliger, Markus A; Schürer, Stephan C; Oakes, Scott A; Papa, Feroz R; Maly, Dustin J
- Abstract
Under endoplasmic reticulum stress, unfolded protein accumulation leads to activation of the endoplasmic reticulum transmembrane kinase/endoRNase (RNase) IRE1?. IRE1? oligomerizes, autophosphorylates and initiates splicing of XBP1 mRNA, thus triggering the unfolded protein response (UPR). Here we show that IRE1?'s kinase-controlled RNase can be regulated in two distinct modes with kinase inhibitors: one class of ligands occupies IRE1?'s kinase ATP-binding site to activate RNase-mediated XBP1 mRNA splicing even without upstream endoplasmic reticulum stress, whereas a second class can inhibit the RNase through the same ATP-binding site, even under endoplasmic reticulum stress. Thus, alternative kinase conformations stabilized by distinct classes of ATP-competitive inhibitors can cause allosteric switching of IRE1?'s RNase-either on or off. As dysregulation of the UPR has been implicated in a variety of cell degenerative and neoplastic disorders, small-molecule control over IRE1? should advance efforts to understand the UPR's role in pathophysiology and to develop drugs for endoplasmic reticulum stress-related diseases.
- Subjects
ALLOSTERIC regulation; ENDOPLASMIC reticulum; RIBONUCLEASES; KINASE inhibitors; PROTEIN folding kinetics; RNA splicing; PHYSIOLOGICAL stress
- Publication
Nature Chemical Biology, 2012, Vol 8, Issue 12, p982
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.1094