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eukaryotic translation initiation factor 2-alpha kinase 3; PRKR-like endoplasmic reticulum kinase; pancreatic eIF2-alpha kinase; HsPEK (EIF2AK3, PEK, PERK)

Function: 1) phosphorylates alpha subunit of eukaryotic translation- initiation factor 2 (eIF2) a) results in inactivation of eIF2 b) rapid reduction of translational initiation c) repression of global protein synthesis 2) effector of unfolded protein response 3) induces G1 growth arrest due to the loss of cyclin D1 4) forms dimers with HSPA5/BIP in resting cells 5) dissociates from HSPA5/BIP & oligomerizes in ER-stressed cells 6) interacts with DNAJC3 7) autophosphorylated Structure: - N-glycosylated - the lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP - belongs to the protein kinase superfamily, Ser/Thr protein kinase family, GCN2 subfamily - contains 1 protein kinase domain Compartment: endoplasmic reticulum Expression: - ubiquitous - induction by ER stress Pathology: - defects are the cause of Wolcott-Rallison syndrome - PERK is activated in the hippocampus of Alzheimer's disease patients & in the pons & medulla of patients with progressive supranuclear palsy [5] - degree of PERK activation seems to be correlated with both age & tau pathology but not with A-beta plaque burden [5] Comparative biology: - in mice, PERK promotes misfolding and halts synthesis of specific proteins [2] - inhibitor of PERK halts progression of prion disease in mice, but does not reverse deficits [2] - inhibition of PERK or reduced expression of PERK improves long-term memory & behavioral plasticity in rats [3]*

General

glycoprotein membrane protein serine/threonine kinase

Properties

SIZE: MW = 125 kD entity length = 1115 aa COMPARTMENT: endoplasmic reticulum MOTIF: signal sequence {1-28} alanine-rich region {48-51} MOTIF: alanine residue (SEVERAL) N-glycosylation site {N257} transmembrane domain {514-534} kinase domain SITE: 592-1076 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 598-606 ATP-binding site NAME: ATP-binding site SITE: 621-621 aspartate residue {D936} STATE: active state

Database Correlations

OMIM correlations MORBIDMAP 604032 UniProt Q9NZJ5 Pfam PF00069 ENZYME 2.7.11.1

References

  1. UniProt :accession Q9NZJ5
  2. Moreno JA et al Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion- Infected Mice. Sci Transl Med. 2013 Oct 9;5(206):206ra138. PMID: 24107777 http://stm.sciencemag.org/content/5/206/206ra138
  3. University of Hafnia. Nov 19, 2014 Researchers Find a Way to Improve Memory by Suppressing a Molecule That Links Aging to Alzheimer's Disease. Journal of Neuroscience, Nov 12, 2014 http://www.newswise.com/articles/view/626415/?sc=mwtn
  4. Ma T, Klann E. PERK: a novel therapeutic target for neurodegenerative diseases? Alzheimers Res Ther. 2014 May 29;6(3):30. PMID: 25031640
  5. Stutzbach LD1, Xie SX, Naj AC et al The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol Commun. 2013 Jul 6;1(1):31. PMID: 24252572