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

Heather P. Harding, Yuhong Zhang and David Ron ()
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Heather P. Harding: Skirball Institute of Biomolecular Medicine, NYU School of Medicine
Yuhong Zhang: Skirball Institute of Biomolecular Medicine, NYU School of Medicine
David Ron: Skirball Institute of Biomolecular Medicine, NYU School of Medicine

Nature, 1999, vol. 397, issue 6716, 271-274

Abstract: 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-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 stress3. 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.

Date: 1999
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DOI: 10.1038/16729

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