EIF2AK3
entrez
9451
canonical
uniprot
Q9NZJ5
canonical
ensembl
ENSG00000172071
resolver
ensp
ENSP00000307235
resolver
ensp
ENSP00000507214
resolver
ensp
ENSP00000507355
resolver
enst
ENST00000303236
resolver
enst
ENST00000682892
resolver
genesymbol
EIF2AK3
resolver
genesymbol_syn
PEK
resolver
genesymbol_syn
PERK
resolver
hgnc
HGNC:3255
resolver
uniprot
A0A804HIT4
resolver
uniprot
A0AVH1
resolver
uniprot
A0AVH2
resolver
uniprot
B2RCU9
resolver
uniprot
B3KY45
resolver
uniprot
O95846
resolver
uniprot
Q53QY0
resolver
uniprot
Q53SB1
resolver
uniprot_entry
A0A804HIT4_HUMAN
resolver
uniprot_entry
B3KY45_HUMAN
resolver
uniprot_entry
E2AK3_HUMAN
resolver
uniprot_sec
A0AVH1
resolver
uniprot_sec
A0AVH2
resolver
uniprot_sec
B2RCU9
resolver
uniprot_sec
O95846
resolver
uniprot_sec
Q53QY0
resolver
uniprot_sec
Q53SB1
resolver
activity_regulation
ACTIVITY REGULATION: Inhibited by HSPA5/BIP in absence of stress (PubMed:11907036). Perturbation in protein folding in the endoplasmic reticulum (ER) promotes reversible dissociation from HSPA5/BIP and oligomerization, resulting in trans-autophosphorylation and kinase activity induction (PubMed:11907036). Inactivated following phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) (By similarity). Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress (PubMed:39116259). {ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:11907036, ECO:0000269|PubMed:39116259}.
uniprot
proteins
amino_acid_sequence
MERAISPGLLVRALLLLLLLLGLAARTVAAGRARGLPAPTAEAAFGLGAAAAPTSATRVPAAGAVAAAEVTVEDAEALPAAAGEQEPRGPEPDDETELRPRGRSLVIISTLDGRIAALDPENHGKKQWDLDVGSGSLVSSSLSKPEVFGNKMIIPSLDGALFQWDQDRESMETVPFTVESLLESSYKFGDDVVLVGGKSLTTYGLSAYSGKVRYICSALGCRQWDSDEMEQEEDILLLQRTQKTVRAVGPRSGNEKWNFSVGHFELRYIPDMETRAGFIESTFKPNENTEESKIISDVEEQEAAIMDIVIKVSVADWKVMAFSKKGGHLEWEYQFCTPIASAWLLKDGKVIPISLFDDTSYTSNDDVLEDEEDIVEAARGATENSVYLGMYRGQLYLQSSVRISEKFPSSPKALESVTNENAIIPLPTIKWKPLIHSPSRTPVLVGSDEFDKCLSNDKFSHEEYSNGALSILQYPYDNGYYLPYYKRERNKRSTQITVRFLDNPHYNKNIRKKDPVLLLHWWKEIVATILFCIIATTFIVRRLFHPHPHRQRKESETQCQTENKYDSVSGEANDSSWNDIKNSGYISRYLTDFEPIQCLGRGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLEAPPEKWQEKMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFATKEHIEIIAPSPQRSRSFSVGISCDQTSSSESQFSPLEFSGMDHEDISESVDAAYNLQDSCLTDCDVEDGTMDGNDEGHSFELCPSEASPYVRSRERTSSSIVFEDSGCDNASSKEEPKTNRLHIGNHCANKLTAFKPTSSKSSSEATLSISPPRPTTLSLDLTKNTTEKLQPSSPKVYLYIQMQLCRKENLKDWMNGRCTIEERERSVCLHIFLQIAEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVTAMDQDEEEQTVLTPMPAYARHTGQVGTKLYMSPEQIHGNSYSHKVDIFSLGLILFELLYPFSTQMERVRTLTDVRNLKFPPLFTQKYPCEYVMVQDMLSPSPMERPEAINIIENAVFEDLDFPGKTVLRQRSRSLSSSGTKHSRQSNNSHSPLPSN
uniprot
proteins
disease_involvement
DISEASE: Wolcott-Rallison syndrome (WRS) [MIM:226980]: 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, intellectual disability and cardiovascular abnormalities. {ECO:0000269|PubMed:10932183, ECO:0000269|PubMed:12086964, ECO:0000269|PubMed:12960215, ECO:0000269|PubMed:16813601, ECO:0000269|PubMed:24168455, ECO:0000269|PubMed:24194294, ECO:0000269|PubMed:27145240, ECO:0000269|PubMed:28220546, ECO:0000269|PubMed:30906465, ECO:0000269|PubMed:30922274, ECO:0000269|PubMed:32216767, ECO:0000269|PubMed:34123975}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.10.2
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR) (PubMed:10026192, PubMed:10677345, PubMed:11907036, PubMed:12086964, PubMed:25925385, PubMed:31023583). Key effector of the integrated stress response (ISR) to unfolded proteins: EIF2AK3/PERK specifically recognizes and binds misfolded proteins, leading to its activation and EIF2S1/eIF-2-alpha phosphorylation (PubMed:10677345, PubMed:27917829, PubMed:31023583). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming (PubMed:10026192, PubMed:10677345, PubMed:31023583, PubMed:33384352). The EIF2AK3/PERK-mediated unfolded protein response increases mitochondrial oxidative phosphorylation by promoting ATF4-mediated expression of COX7A2L/SCAF1, thereby increasing formation of respiratory chain supercomplexes (PubMed:31023583). In contrast to most subcellular compartments, mitochondria are protected from the EIF2AK3/PERK-mediated unfolded protein response due to EIF2AK3/PERK inhibition by ATAD3A at mitochondria-endoplasmic reticulum contact sites (PubMed:39116259). In addition to EIF2S1/eIF-2-alpha, also phosphorylates NFE2L2/NRF2 in response to stress, promoting release of NFE2L2/NRF2 from the BCR(KEAP1) complex, leading to nuclear accumulation and activation of NFE2L2/NRF2 (By similarity). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (By similarity). Involved in control of mitochondrial morphology and function (By similarity). {ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:10026192, ECO:0000269|PubMed:10677345, ECO:0000269|PubMed:11907036, ECO:0000269|PubMed:12086964, ECO:0000269|PubMed:25925385, ECO:0000269|PubMed:27917829, ECO:0000269|PubMed:31023583, ECO:0000269|PubMed:33384352, ECO:0000269|PubMed:39116259}.
uniprot
proteins
mass_dalton
125216
uniprot
proteins
mutagenesis
MUTAGEN 164; /note="W->A: Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha."; /evidence="ECO:0000269|PubMed:25925385"; MUTAGEN 388; /note="L->N: Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha."; /evidence="ECO:0000269|PubMed:25925385"; MUTAGEN 395; /note="L->N: Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha."; /evidence="ECO:0000269|PubMed:25925385"; MUTAGEN 397; /note="L->N: Decreased tetramerization and activation, leading to decreased ability to phosphorylate EIF2S1/eIF-2-alpha."; /evidence="ECO:0000269|PubMed:25925385
uniprot
proteins
post_translational_modification
PTM: Oligomerization of the N-terminal ER luminal domain by ER stress promotes EIF2AK3/PERK trans-autophosphorylation of the C-terminal cytoplasmic kinase domain at multiple residues including Thr-982 on the kinase activation loop (By similarity). Autophosphorylated at Tyr-619 following endoplasmic reticulum stress, leading to activate its activity (PubMed:22169477). Dephosphorylated at Tyr-619 by PTPN1/PTP1B, leading to inactivate its enzyme activity (PubMed:22169477). Phosphorylation at Thr-802 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (By similarity). {ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:22169477}.; PTM: ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity. {ECO:0000269|PubMed:23103912}.
uniprot
proteins
protein_family
GCN2 subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
Ser/Thr protein kinase family
uniprot
proteins
pubmed
10026192
uniprot
proteins
pubmed
10677345
uniprot
proteins
pubmed
10932183
uniprot
proteins
pubmed
11907036
uniprot
proteins
pubmed
12086964
uniprot
proteins
pubmed
12960215
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15815621
uniprot
proteins
pubmed
16813601
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
22169477
uniprot
proteins
pubmed
23103912
uniprot
proteins
pubmed
24168455
uniprot
proteins
pubmed
24194294
uniprot
proteins
pubmed
24508390
uniprot
proteins
pubmed
25925385
uniprot
proteins
pubmed
26268696
uniprot
proteins
pubmed
27145240
uniprot
proteins
pubmed
27917829
uniprot
proteins
pubmed
28220546
uniprot
proteins
pubmed
30906465
uniprot
proteins
pubmed
30922274
uniprot
proteins
pubmed
31023583
uniprot
proteins
pubmed
31875558
uniprot
proteins
pubmed
32216767
uniprot
proteins
pubmed
33384352
uniprot
proteins
pubmed
34123975
uniprot
proteins
pubmed
39116259
uniprot
proteins
sequence_length
1116
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9Z2B5}; Single-pass type I membrane protein {ECO:0000255}. Note=Localizes to the Localizes to endoplasmic reticulum membrane (By similarity). Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (PubMed:39116259). {ECO:0000250|UniProtKB:Q9Z2B5, ECO:0000269|PubMed:39116259}.
uniprot
proteins
transmembrane_region
TRANSMEM 515..535; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins