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Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1
Open accessAbstract
Summary Signaling in the most conserved branch of the endoplasmic reticulum (ER) unfolded protein response (UPR) is initiated by sequence-specific cleavage of the HAC1/XBP1 mRNA by the ER stress-induced kinase-endonuclease IRE1. We have discovered that the flavonol quercetin activates yeast IRE1’s RNase and potentiates activation by ADP, a natural activating ligand that engages the IRE1 nucleotide binding cleft. Enzyme kinetics and the structure of a co-crystal of IRE1 complexed with ADP and quercetin reveal engagement by quercetin of an unanticipated ligand binding pocket at the dimer interface of IRE1’s Kinase Extension Nuclease (KEN) domain. Analytical ultracentrifugation and crosslinking studies support the preeminence of enhanced dimer formation in quercetin’s mechanism of action. These findings hint at the existence of endogenous cytoplasmic ligands that may function alongside stress signals from the ER lumen to modulate IRE1 activity and at the potential for the development of drugs that modify UPR signaling from this unanticipated site.
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Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Biological and Chemical Approaches to Diseases of Proteostasis Deficiency
Powers, E. T., Morimoto, R. I., Dillin, A., Kelly, J. W., & Balch, W. E. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.052308.114844 · Cited by 1,149
Orchestrating the unfolded protein response in health and disease
Kaufman, R. J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216886 · Cited by 1,015
The unfolded protein response signals through high-order assembly of Ire1
Korennykh, A. V., Egea, P. F., Korostelev, A. A., Finer-Moore, J., Zhang, C., Shokat, K. M., Stroud, R. M., & Walter, P. (2009) · Nature · doi:10.1038/nature07661 · Cited by 656
Sriburi, R., Jackowski, S., Mori, K., & Brewer, J. W. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200406136 · Cited by 653
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Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications
Almanza, A., Carlesso, A., Chintha, C., Creedican, S., Doultsinos, D., Leuzzi, B., Luís, A., McCarthy, N., Montibeller, L., More, S., et al. (2019) · The FEBS Journal · doi:10.1111/febs.14608 · Cited by 1,034
Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response
Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M., & Walter, P. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a013169 · Cited by 721
The flavonoid quercetin in disease prevention and therapy: Facts and fancies
Russo, M., Spagnuolo, C., Tedesco, I., Bilotto, S., & Russo, G. L. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.08.010 · Cited by 698
Papandreou, I., Denko, N. C., Olson, M., Van Melckebeke, H., Lust, S., Tam, A., Solow-Cordero, D. E., Bouley, D. M., Offner, F., Niwa, M., et al. (2011) · Blood · doi:10.1182/blood-2010-08-303099 · Cited by 489
Sidrauski, C., Tsai, J. C., Kampmann, M., Hearn, B. R., Vedantham, P., Jaishankar, P., Sokabe, M., Mendez, A. S., Newton, B. W., Tang, E. L., et al. (2015) · eLife · doi:10.7554/elife.07314 · Cited by 256
Metadata
- Authors
- Wiseman, R. L., Zhang, Y., Lee, K. P. K., Harding, H. P., Haynes, C. M., Price, J., Sicheri, F., & Ron, D.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 38
- Issue
- 2
- Pages
- 291-304
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1974854199
- Cited by
- 190
- References
- 5
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Wiseman, R. L., Zhang, Y., Lee, K. P. K., Harding, H. P., Haynes, C. M., Price, J., Sicheri, F., & Ron, D. (2010). Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1. Molecular Cell. https://doi.org/10.1016/j.molcel.2010.04.001
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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