Abstract
The unfolded protein response (UPR) detects the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and adjusts the protein-folding capacity to the needs of the cell. Under conditions of ER stress, the transmembrane protein Ire1 oligomerizes to activate its cytoplasmic kinase and ribonuclease domains. It is unclear what feature of ER stress Ire1 detects. We found that the core ER-lumenal domain (cLD) of yeast Ire1 binds to unfolded proteins in yeast cells and to peptides primarily composed of basic and hydrophobic residues in vitro. Mutation of amino acid side chains exposed in a putative peptide-binding groove of Ire1 cLD impaired peptide binding. Peptide binding caused Ire1 cLD oligomerization in vitro, suggesting that direct binding to unfolded proteins activates the UPR.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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Cathepsin A / chemistry
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Cathepsin A / metabolism
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Endoplasmic Reticulum / metabolism*
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Fluorescence Polarization
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Fungal Proteins / chemistry
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Fungal Proteins / metabolism
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Glutathione Transferase / metabolism
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HSP70 Heat-Shock Proteins / chemistry
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HSP70 Heat-Shock Proteins / metabolism
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Hydrophobic and Hydrophilic Interactions
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Ligands
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Membrane Glycoproteins / chemistry*
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Membrane Glycoproteins / metabolism*
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Protein Binding
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Protein Conformation
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Protein Folding
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / metabolism*
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Stress, Physiological
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Unfolded Protein Response*
Substances
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Fungal Proteins
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HSP70 Heat-Shock Proteins
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KAR2 protein, yeast
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Ligands
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Membrane Glycoproteins
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Mutant Proteins
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Saccharomyces cerevisiae Proteins
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Glutathione Transferase
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IRE1 protein, S cerevisiae
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Protein Serine-Threonine Kinases
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Cathepsin A