The structure of the PERK kinase domain suggests the mechanism for its activation

Journal Article · Sun May 01 04:00:00 EDT 2011 · Acta Crystallographica. Section D: Biological Crystallography

DOI:https://doi.org/10.1107/S0907444911006445· OSTI ID:22351226

Cui, Wenjun; Li, Jingzhi ^[1]; Ron, David ^[2]; Sha, Bingdong ^[1]

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1. University of Alabama at Birmingham, Birmingham, AL 35294 (United States)
2. University of Cambridge, Cambridge CB2 0QQ (United Kingdom)

The endoplasmic reticulum-localized transmembrane kinase PERK is one of three major ER stress transducers. The crystal structure of PERK’s kinase domain has been determined to 2.8 Å resolution. The endoplasmic reticulum (ER) unfolded protein response (UPR) is comprised of several intracellular signaling pathways that alleviate ER stress. The ER-localized transmembrane kinase PERK is one of three major ER stress transducers. Oligomerization of PERK’s N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr980 on the kinase activation loop. Activated PERK phosphorylates Ser51 of the α-subunit of translation initiation factor 2 (eIF2α), which inhibits initiation of protein synthesis and reduces the load of unfolded proteins entering the ER. The crystal structure of PERK’s kinase domain has been determined to 2.8 Å resolution. The structure resembles the back-to-back dimer observed in the related eIF2α kinase PKR. Phosphorylation of Thr980 stabilizes both the activation loop and helix αG in the C-terminal lobe, preparing the latter for eIF2α binding. The structure suggests conservation in the mode of activation of eIF2α kinases and is consistent with a ‘line-up’ model for PERK activation triggered by oligomerization of its luminal domain.

• OSTI ID: 22351226
• Journal Information: Acta Crystallographica. Section D: Biological Crystallography, Journal Name: Acta Crystallographica. Section D: Biological Crystallography Journal Issue: Pt 5 Vol. 67; ISSN ABCRE6; ISSN 0907-4449
• Country of Publication: Denmark
• Language: English

Related Subjects

75 CONDENSED MATTER PHYSICS
SUPERCONDUCTIVITY AND SUPERFLUIDITY
CRYSTAL STRUCTURE
DIMERS
RESOLUTION
SYNTHESIS