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Published 17 January 2006. doi:10.1083/jcb.200508099
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 2, 201-209
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Article

 Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK

Stefan J. Marciniak1, Lidia Garcia-Bonilla1, Junjie Hu1, Heather P. Harding1,2, and David Ron1,3,4

1 Skirball Institute of Biomolecular Medicine, 2 Department of Pharmacology, 3 Department of Medicine, and 4 Department of Cell Biology, New York University School of Medicine, New York, NY 10016

Correspondence to David Ron: ron{at}saturn.med.nyu.edu

Regulated phosphorylation of the {alpha} subunit of eukaryotic translation initiation factor 2 (eIF2{alpha}) by the endoplasmic reticulum (ER) stress-activated protein kinase PERK modulates protein synthesis and couples the production of ER client proteins with the organelle's capacity to fold and process them. PERK activation by ER stress is known to involve transautophosphorylation, which decorates its unusually long kinase insert loop with multiple phosphoserine and phosphothreonine residues. We report that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex. This switch correlates with a marked change to the protease sensitivity pattern, which is indicative of a major conformational change in the PERK kinase domain upon activation. Although it is dispensable for catalytic activity, PERK's kinase insert loop is required for substrate binding and for eIF2{alpha} phosphorylation in vivo. Our findings suggest a novel mechanism for eIF2 recruitment by activated PERK and for unidirectional substrate flow in the phosphorylation reaction.

S.J. Marciniak's present address is Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, UK.

Abbreviations used in this paper: eIF, eukaryotic translation initiation factor; NTA, nitrilotriacetic acid; NTD, NH2-terminal domain; UPRer, ER unfolded protein response.


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