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

By A. Korennykh, P. Egea, A. Korostelev, J. Finer-Moore, Chao Zhang, Kevan M. Shokat, R. Stroud, Peter Walter. Nature, 2008

639 citations recorded by the source corpus.

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-Å 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3f48967b7f9efd611586f1bedc9437a303137367

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. C. Hetz
2. F. Papa
3. Peter Walter
4. Scott A Oakes
5. Afshin Samali
6. A. Gorman
7. Han Li
8. B. Gardner

In Molecular Biology

1. C. Hetz
2. F. Papa
3. Peter Walter
4. E. Gilbert
5. Zhuo Fu
6. Sanjeev Gupta
7. Dongmin Liu
8. Jonathan S. Weissman

Citations in the corpus

• The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, background): “Further oligomerization of IRE1 into large clusters correlates with the kinetics of its autophosphorylation and the subsequent initiation of its ability to splice XBP1 mRNA in mammals or HAC1 mRNA in yeas”
• Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes (2012, positive): “The IRE1 is a kinase/endoribonuclease that splices XBP-1 mRNA, which is then translated into a bZIP transcription factor that induces transcription of protein-folding-related genes [491, 493].”
• The eIF2α kinases: their structures and functions (2013, positive): “Indeed, as mentioned above, constitutively active PERK has been shown to promote apoptotic cell death [116], and PERK activation and signaling (in the absence of ATF6 and IRE1 activation) has been suggested to represent the terminal , pro-apoptotic phase of the UPR in response to prolonged ER stress”
• Regulated Ire1-dependent decay of messenger RNAs in mammalian cells (2009, background): “For example, it was recently found that yeast Ire1 forms higher order oligomers that lead to higher levels of RNase activity (Aragon et al., 2009; Korennykh et al., 2009).”
• Endoplasmic reticulum stress sensing in the unfolded protein response. (2013, background): “Crystal structures of the yeast kinase/RNase domains suggest that Ire1 first associates into backto-back dimers, followed by assembly into higher-orderoligomers that stabilize the RNase active site through oligomer-specific protein/protein interfaces (Lee et al. 2008; Korennykh et al. 2009).”
• IRE1α Kinase Activation Modes Control Alternate Endoribonuclease Outputs to Determine Divergent Cell Fates (2009, positive): “The RNase catalytic pocket in oligomeric IRE1 is larger than in dimeric IRE1, and exhibits catalytic rates that are orders of magnitude higher than that of dimers (Korennykh et al., 2009).”