The structure of the PERK kinase domain suggests the mechanism for its activation
- UAB
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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- NIHU.S. ARMY RESEARCH
- OSTI ID:
- 1040896
- Journal Information:
- Acta Crystallogr. D, Vol. 67, Issue (5) ; 05, 2011; ISSN 0907-4449
- Country of Publication:
- United States
- Language:
- ENGLISH
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