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Title: Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1

Abstract

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 cocrystal 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.

Authors:
; ; ; ; ; ; ;  [1]
  1. Scripps
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002467
Resource Type:
Journal Article
Journal Name:
Mol. Cell
Additional Journal Information:
Journal Volume: 38; Journal Issue: (2) ; 04, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CLEAVAGE; DIMERS; ENDOPLASMIC RETICULUM; ENZYMES; KINETICS; NUCLEASES; PHOSPHOTRANSFERASES; PROTEINS; QUERCETIN; ULTRACENTRIFUGATION; YEASTS

Citation Formats

Wiseman, R Luke, Zhang, Yuhong, Lee, Kenneth P.K., Harding, Heather P, Haynes, Cole M, Price, Joshua, Sicheri, Frank, Ron, David, Toronto), and NYUSM). Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1. United States: N. p., 2010. Web. doi:10.1016/j.molcel.2010.04.001.
Wiseman, R Luke, Zhang, Yuhong, Lee, Kenneth P.K., Harding, Heather P, Haynes, Cole M, Price, Joshua, Sicheri, Frank, Ron, David, Toronto), & NYUSM). Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1. United States. https://doi.org/10.1016/j.molcel.2010.04.001
Wiseman, R Luke, Zhang, Yuhong, Lee, Kenneth P.K., Harding, Heather P, Haynes, Cole M, Price, Joshua, Sicheri, Frank, Ron, David, Toronto), and NYUSM). 2010. "Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1". United States. https://doi.org/10.1016/j.molcel.2010.04.001.
@article{osti_1002467,
title = {Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1},
author = {Wiseman, R Luke and Zhang, Yuhong and Lee, Kenneth P.K. and Harding, Heather P and Haynes, Cole M and Price, Joshua and Sicheri, Frank and Ron, David and Toronto) and NYUSM)},
abstractNote = {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 cocrystal 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.},
doi = {10.1016/j.molcel.2010.04.001},
url = {https://www.osti.gov/biblio/1002467}, journal = {Mol. Cell},
number = (2) ; 04, 2010,
volume = 38,
place = {United States},
year = {Wed Aug 18 00:00:00 EDT 2010},
month = {Wed Aug 18 00:00:00 EDT 2010}
}