Publication Date:
2003-10-18
Description:
Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylation of the bifunctional transmembrane kinase Ire1, which induces its endoribonuclease activity. The endoribonuclease initiates nonconventional splicing of HAC1 messenger RNA to trigger the unfolded-protein response (UPR). We explored the role of Ire1's kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized Ire1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Papa, Feroz R -- Zhang, Chao -- Shokat, Kevan -- Walter, Peter -- AI44009/AI/NIAID NIH HHS/ -- GM32384/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Nov 28;302(5650):1533-7. Epub 2003 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of California, San Francisco, CA 94143-2200, USA. frpapa@medicine.ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14564015" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Diphosphate/pharmacology
;
Adenosine Triphosphate/analogs & derivatives/chemistry/*metabolism/pharmacology
;
Basic-Leucine Zipper Transcription Factors
;
Binding Sites
;
Binding, Competitive
;
Cytosol/metabolism
;
Dithiothreitol/pharmacology
;
Endoplasmic Reticulum/*metabolism
;
Endoribonucleases/metabolism
;
Enzyme Activation
;
Ligands
;
Membrane Glycoproteins/antagonists & inhibitors/*chemistry/genetics/*metabolism
;
Models, Biological
;
Mutagenesis, Site-Directed
;
Phosphorylation
;
Protein Conformation
;
*Protein Folding
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/antagonists &
;
inhibitors/*chemistry/genetics/*metabolism
;
Pyrazoles/chemistry/*metabolism/*pharmacology
;
Pyrimidines/chemistry/*metabolism/*pharmacology
;
RNA Splicing
;
RNA, Messenger/genetics/metabolism
;
Repressor Proteins/genetics/metabolism
;
Saccharomyces cerevisiae Proteins/antagonists &
;
inhibitors/*chemistry/genetics/*metabolism
;
Signal Transduction
;
Structure-Activity Relationship
;
Substrate Specificity
;
Transcription Factors/genetics/metabolism
;
Up-Regulation
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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