Abstract
Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
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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3T3 Cells
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Amino Acid Sequence
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Animals
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COS Cells
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Caenorhabditis elegans / enzymology
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Caenorhabditis elegans / genetics
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Cloning, Molecular
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Endoplasmic Reticulum / enzymology*
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Escherichia coli
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Eukaryotic Initiation Factor-2 / chemistry
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Eukaryotic Initiation Factor-2 / metabolism
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Fungal Proteins / chemistry
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Fungal Proteins / metabolism
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Gene Expression Regulation
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Humans
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Intracellular Membranes / enzymology
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / metabolism
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Mice
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Molecular Sequence Data
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Protein Biosynthesis*
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Protein Folding*
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Protein Serine-Threonine Kinases*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae Proteins*
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Sequence Homology, Amino Acid
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Signal Transduction
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eIF-2 Kinase / chemistry
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eIF-2 Kinase / genetics*
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eIF-2 Kinase / physiology
Substances
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Eukaryotic Initiation Factor-2
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Fungal Proteins
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Membrane Glycoproteins
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae Proteins
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IRE1 protein, S cerevisiae
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase