Publication Date:
2008-12-17
Description:
Aberrant folding of proteins in the endoplasmic reticulum activates the bifunctional transmembrane kinase/endoribonuclease Ire1. Ire1 excises an intron from HAC1 messenger RNA in yeasts and Xbp1 messenger RNA in metozoans encoding homologous transcription factors. This non-conventional mRNA splicing event initiates the unfolded protein response, a transcriptional program that relieves the endoplasmic reticulum stress. Here we show that oligomerization is central to Ire1 function and is an intrinsic attribute of its cytosolic domains. We obtained the 3.2-A crystal structure of the oligomer of the Ire1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the Ire1 RNase. The structure reveals a rod-shaped assembly that has no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signalling receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846394/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Korennykh, Alexei V -- Egea, Pascal F -- Korostelev, Andrei A -- Finer-Moore, Janet -- Zhang, Chao -- Shokat, Kevan M -- Stroud, Robert M -- Walter, Peter -- R01 GM060641/GM/NIGMS NIH HHS/ -- R01 GM060641-01/GM/NIGMS NIH HHS/ -- R01 GM60641/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Feb 5;457(7230):687-93. doi: 10.1038/nature07661. Epub 2008 Dec 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94158, USA. alexei.korennykh@ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19079236" target="_blank"〉PubMed〈/a〉
Keywords:
Basic-Leucine Zipper Transcription Factors/genetics
;
Binding Sites
;
Crystallography, X-Ray
;
Cytosol/metabolism
;
Enzyme Activation/drug effects
;
Introns/genetics
;
Membrane Glycoproteins/antagonists & inhibitors/*chemistry/*metabolism
;
Models, Molecular
;
Phosphorylation/drug effects
;
Protein Binding/drug effects
;
Protein Denaturation
;
*Protein Folding
;
Protein Kinase Inhibitors/chemistry/metabolism/pharmacology
;
Protein Multimerization
;
Protein Structure, Quaternary
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism
;
Repressor Proteins/genetics
;
Ribonucleases/chemistry/metabolism
;
Saccharomyces cerevisiae/*chemistry/*enzymology
;
Saccharomyces cerevisiae Proteins/antagonists &
;
inhibitors/*chemistry/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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