The unfolded protein response signals through high-order assembly of Ire1

被引:489
作者
Korennykh, Alexei V. [1 ,3 ]
Egea, Pascal F. [1 ]
Korostelev, Andrei A. [4 ]
Finer-Moore, Janet [1 ]
Zhang, Chao [2 ,3 ]
Shokat, Kevan M. [2 ,3 ]
Stroud, Robert M. [1 ]
Walter, Peter [1 ,3 ]
机构
[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA
[3] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA
[4] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA
关键词
ENDOPLASMIC-RETICULUM; MESSENGER-RNA; ER-STRESS; KINASE; MECHANISM; AUTOPHOSPHORYLATION; ACTIVATION; SOFTWARE;
D O I
10.1038/nature07661
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:687 / U2
页数:8
相关论文
共 35 条
[1]   PHENIX:: building new software for automated crystallographic structure determination [J].
Adams, PD ;
Grosse-Kunstleve, RW ;
Hung, LW ;
Ioerger, TR ;
McCoy, AJ ;
Moriarty, NW ;
Read, RJ ;
Sacchettini, JC ;
Sauter, NK ;
Terwilliger, TC .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2002, 58 :1948-1954
[2]   RETRACTED: Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis (Retracted Article) [J].
Atkin, Julie D. ;
Farg, Manal A. ;
Walker, Adam K. ;
McLean, Catriona ;
Tomas, Doris ;
Horne, Malcolm K. .
NEUROBIOLOGY OF DISEASE, 2008, 30 (03) :400-407
[3]   Activation of the unfolded protein response by ΔF508 CFTR [J].
Bartoszewski, Rafal ;
Rab, Andras ;
Jurkuvenaite, Asta ;
Mazur, Marina ;
Wakefield, John ;
Collawn, James F. ;
Bebok, Zsuzsa .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2008, 39 (04) :448-457
[4]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[5]   A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response [J].
Cox, JS ;
Walter, P .
CELL, 1996, 87 (03) :391-404
[6]   On the mechanism of sensing unfolded protein in the endoplasmic reticulum [J].
Credle, JJ ;
Finer-Moore, JS ;
Papa, FR ;
Stroud, RM ;
Walter, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (52) :18773-18784
[7]   A kinase inhibitor activates the IRE1α RNase to confer cytoprotection against ER stress [J].
Dan, Han ;
Upton, John-Paul ;
Hagen, Andrew ;
Callahan, Joseph ;
Oakes, Scott A. ;
Papa, Feroz R. .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 365 (04) :777-783
[8]   Coot:: model-building tools for molecular graphics [J].
Emsley, P ;
Cowtan, K .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132
[9]   Scaling and assessment of data quality [J].
Evans, P .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2006, 62 :72-82
[10]   Bias in cross-validated free R factors:: mitigation of the effects of non-crystallographic symmetry [J].
Fabiola, F ;
Korostelev, A ;
Chapman, MS .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2006, 62 :227-238