Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

• Published in: Nature (London) 1999-01, Vol.397 (6716), p.271-274
• Main Authors: Harding, Heather P., Zhang, Yuhong, Ron, David
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Amino Acid Sequence; Animals; Biological and medical sciences; Caenorhabditis elegans - enzymology; Caenorhabditis elegans - genetics; Cell physiology; Cellular biology; Cloning; Cloning, Molecular; COS Cells; eIF-2 Kinase - chemistry; eIF-2 Kinase - genetics; eIF-2 Kinase - physiology; Endoplasmic Reticulum - enzymology; Escherichia coli; Eukaryotic Initiation Factor-2 - chemistry; Eukaryotic Initiation Factor-2 - metabolism; Fundamental and applied biological sciences. Psychology; Fungal Proteins - chemistry; Fungal Proteins - metabolism; Gene Expression Regulation; Genes; Humanities and Social Sciences; Humans; Intracellular Membranes - enzymology; letter; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mice; Molecular and cellular biology; Molecular Sequence Data; multidisciplinary; Protein Biosynthesis; Protein Folding; Protein synthesis; Protein-Serine-Threonine Kinases; Proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Saccharomyces cerevisiae Proteins; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Signal Transduction
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/16729

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-2α (eIF2α) in response to a stress signal from the endoplasmic reticulum (ER) 1 , 2 . Activation of this process leads to reduced rates of initiation of protein translation during ER stress 3 . 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 eIF2α kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2α 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.