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

Nature volume 397, pages 271–274 (1999)Cite this article

An Erratum to this article was published on 04 March 1999

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.

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Figure 1: perk encodes an ER-resident protein with similarity to Ire1 and PKR.
Figure 2: PERK is an eIF2α kinase that inhibits translation.
Figure 3: PERK is activated by ER stress.

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Acknowledgements

We thank R. Schneider for the eIF2α expression plasmids, antisera and purified protein; M. Green for the immunoglobulin µ-chain expression plasmid; B. Williams for the pkr−/− cells; G.Kreibich for the antisera against ribophorin; and X.-Z. Wang for the cDNA libary. This work was supported by NIH grants and an NIH training grant (to H.P.H.). D.R. is a Stephen Birnbaum Scholar of the Leukemia Society of America.

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  1. Departments of Medicine and Cell Biology and the Kaplan Cancer Center, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, 10016, New York, USA

    Heather P. Harding, Yuhong Zhang & David Ron

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Correspondence to David Ron.

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Harding, H., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999). https://doi.org/10.1038/16729

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