title: The structure of the PERK kinase domain suggests the mechanism for its activation.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Cui
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Bingdong
authors.initials: B
authors.lastname: Sha
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D019892:eIF-2 Kinase