File(s) not publicly available
Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response
journal contribution
posted on 2023-06-08, 07:45 authored by MMU Ali, T Bagratuni, EL Davenport, PR Nowak, MC Silva-Santiestaban, A Hardcastle, C McAndrews, MG Rowlands, GJ Morgan, W Aherne, I Collins, FE Davies, Laurence PearlLaurence PearlIre1 (Ern1) is an unusual transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR). Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1 bound to ADP, revealing the phosphoryl-transfer competent dimeric face-to-face complex, which precedes and is distinct from the back-to-back RNase active conformation described for yeast Ire1. We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation, and that ATP-competitive inhibitors staurosporin and sunitinib, which inhibit autophosphorylation in vitro, also inhibit Xbp1 splicing in vivo. Furthermore, we demonstrate that activated Ire1 is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. These studies identify human Ire1 as a target for development of ATP-competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies.
History
Publication status
- Published
Journal
EMBO JournalISSN
0261-4189Publisher
Nature Publishing GroupExternal DOI
Issue
5Volume
30Page range
894-905Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC