Cui Wenjun, Li Jingzhi, Ron David, Sha Bingdong
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):423-8. doi: 10.1107/S0907444911006445. Epub 2011 Apr 13.
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.
内质网（ER）未折叠蛋白反应（UPR）由几种减轻内质网应激的细胞内信号通路组成。内质网定位的跨膜激酶PERK是三种主要的内质网应激转导因子之一。内质网应激导致PERK的N端内质网腔结构域寡聚化，促进PERK在包括激酶激活环上的Thr980在内的多个残基处对C端胞质激酶结构域进行自身磷酸化。激活的PERK使翻译起始因子2（eIF2α）的α亚基的Ser51磷酸化，从而抑制蛋白质合成的起始并减少进入内质网的未折叠蛋白的负荷。PERK激酶结构域的晶体结构已确定分辨率为2.8 Å。该结构类似于在相关的eIF2α激酶PKR中观察到的背对背二聚体。Thr980的磷酸化稳定了C端叶中的激活环和αG螺旋，为后者与eIF2α结合做好准备。该结构表明eIF2α激酶激活模式具有保守性，并且与由其腔结构域寡聚化触发的PERK激活的“排列”模型一致。
