Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response

Ali, MMU, Bagratuni, T, Davenport, EL, Nowak, PR, Silva-Santiestaban, MC, Hardcastle, A, McAndrews, C, Rowlands, MG, Morgan, GJ, Aherne, W, Collins, I, Davies, FE and Pearl, Laurence (2011) Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. EMBO Journal, 30 (5). pp. 894-905. ISSN 0261-4189

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Abstract

Ire1 (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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
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Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 20:46
Last Modified: 08 Oct 2012 11:09
URI: http://srodev.sussex.ac.uk/id/eprint/28031
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