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

An Erratum to this article was published on 04 March 1999


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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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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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).

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