Abstract
PERK and IRE1 are type-I transmembrane protein kinases that reside in the endoplasmic reticulum (ER) and transmit stress signals in response to perturbation of protein folding. Here we show that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenal domains form a stable complex with the ER chaperone BiP. Perturbation of protein folding promotes reversible dissociation of BiP from the lumenal domains of PERK and IRE1. Loss of BiP correlates with the formation of high-molecular-mass complexes of activated PERK or IRE1, and overexpression of BiP attenuates their activation. These findings are consistent with a model in which BiP represses signalling through PERK and IRE1 and protein misfolding relieves this repression by effecting the release of BiP from the PERK and IRE1 lumenal domains.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / isolation & purification
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Carrier Proteins / metabolism*
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Cell Line
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Cricetinae
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Dithiothreitol / pharmacology
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Endoplasmic Reticulum / chemistry*
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum Chaperone BiP
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Enzyme Activation / drug effects
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Heat-Shock Proteins*
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Membrane Proteins*
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Mice
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Models, Biological
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Molecular Chaperones / chemistry
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Molecular Chaperones / genetics
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Molecular Chaperones / isolation & purification
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Molecular Chaperones / metabolism*
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Molecular Weight
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Phosphorylation / drug effects
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Precipitin Tests
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Protein Binding / drug effects
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Protein Folding*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Rats
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
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Thapsigargin / pharmacology
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Thermodynamics
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Transfection
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eIF-2 Kinase / chemistry
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eIF-2 Kinase / isolation & purification
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eIF-2 Kinase / metabolism*
Substances
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Carrier Proteins
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Endoplasmic Reticulum Chaperone BiP
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Heat-Shock Proteins
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Membrane Proteins
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Molecular Chaperones
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Recombinant Fusion Proteins
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Thapsigargin
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Ern2 protein, mouse
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Ern2 protein, rat
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Dithiothreitol