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

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 alpha-subunit of translation initiation factor 2 (eIF2 alpha), 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 angstrom resolution. The structure resembles the back-to-back dimer observed in the related eIF2 alpha kinase PKR. Phosphorylation of Thr980 stabilizes both the activation loop and helix alpha G in the C-terminal lobe, preparing the latter for eIF2 alpha binding. The structure suggests conservation in the mode of activation of eIF2 alpha kinases and is consistent with a 'line-up' model for PERK activation triggered by oligomerization of its luminal domain.