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

DOI: 10.1038/emboj.2011.18 DOI Help
PMID: 21317875 PMID Help

Authors: Maruf M. U. Ali (Imperial College London) , Tina Bagratuni (The Institute of Cancer Research) , Emma L. Davenport (The Institute of Cancer Research) , Piotr R. Nowak (Imperial College London) , M. Cris Silva-Santisteban (Institute of Cancer Research) , Anthea Hardcastle (The Institute of Cancer Research) , Craig Mcandrews (The Institute of Cancer Research) , Martin G. Rowlands (The Institute of Cancer Research) , Gareth J. Morgan (The Institute of Cancer Research) , Wynne Aherne (The Institute of Cancer Research) , Ian Collins (The Institute of Cancer Research) , Faith E. Davies (Institute of Cancer Research) , Laurence H. Pearl (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 30 (5) , PAGES 894 - 905

State: Published (Approved)
Published: February 2011
Diamond Proposal Number(s): 6385

Open Access Open Access

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.

Journal Keywords: Western; Cell; Crystallography; X-Ray; Cytoplasm; DNA-Binding; Endoplasmic; Endoribonucleases; Gene; Humans; Membrane; Phosphorylation; Protein; Protein-Serine-Threonine; RNA; RNA; Messenger; Reverse; Transcription; Transcription; Genetic; Unfolded Protein Response

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 29/09/2011 17:55

The EMBO Journal - 2011 - Ali - Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein.pdf

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)