ID:E2AK3_HUMAN DESCRIPTION: RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 3; EC=2.7.11.1; AltName: Full=PRKR-like endoplasmic reticulum kinase; AltName: Full=Pancreatic eIF2-alpha kinase; Short=HsPEK; Flags: Precursor; FUNCTION: Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in transautophosphorylation and kinase activity induction (By similarity). SUBUNIT: Forms dimers with HSPA5/BIP in resting cells. Oligomerizes in ER-stressed cells. Interacts with DNAJC3 (By similarity). INTERACTION: Self; NbExp=2; IntAct=EBI-766076, EBI-766076; SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass type I membrane protein. TISSUE SPECIFICITY: Ubiquitous. A high level expression is seen in secretory tissues. INDUCTION: By endoplasmic reticulum stress. DOMAIN: The lumenal domain senses perturbations in protein folding in the ER, probably through reversible interaction with HSPA5/BIP (By similarity). PTM: Oligomerization of the N-terminal ER luminal domain by ER stress promotes PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity). Autophosphorylated. Phosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity. PTM: N-glycosylated (By similarity). DISEASE: Defects in EIF2AK3 are the cause of Wolcott-Rallison syndrome (WRS) [MIM:226980]; also known as multiple epiphyseal dysplasia with early-onset diabetes mellitus. WRS is a rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/EIF2AK3";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9NZJ5
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001501 skeletal system development GO:0001503 ossification GO:0001525 angiogenesis GO:0002063 chondrocyte development GO:0006417 regulation of translation GO:0006468 protein phosphorylation GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0006983 ER overload response GO:0006986 response to unfolded protein GO:0007029 endoplasmic reticulum organization GO:0010575 positive regulation of vascular endothelial growth factor production GO:0010628 positive regulation of gene expression GO:0010998 regulation of translational initiation by eIF2 alpha phosphorylation GO:0016310 phosphorylation GO:0017148 negative regulation of translation GO:0018105 peptidyl-serine phosphorylation GO:0019722 calcium-mediated signaling GO:0030282 bone mineralization GO:0030968 endoplasmic reticulum unfolded protein response GO:0031018 endocrine pancreas development GO:0031642 negative regulation of myelination GO:0032055 negative regulation of translation in response to stress GO:0032057 negative regulation of translational initiation in response to stress GO:0034198 cellular response to amino acid starvation GO:0034976 response to endoplasmic reticulum stress GO:0036492 eiF2alpha phosphorylation in response to endoplasmic reticulum stress GO:0036499 PERK-mediated unfolded protein response GO:0042149 cellular response to glucose starvation GO:0045943 positive regulation of transcription from RNA polymerase I promoter GO:0046777 protein autophosphorylation GO:0048009 insulin-like growth factor receptor signaling pathway GO:0051260 protein homooligomerization GO:0060734 regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation GO:0070417 cellular response to cold GO:1900182 positive regulation of protein localization to nucleus GO:1902235 regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway GO:1990737 response to manganese-induced endoplasmic reticulum stress
Cellular Component: GO:0005737 cytoplasm GO:0005783 endoplasmic reticulum GO:0005789 endoplasmic reticulum membrane GO:0016020 membrane GO:0016021 integral component of membrane GO:0030176 integral component of endoplasmic reticulum membrane GO:0048471 perinuclear region of cytoplasm
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
