Eif2ak3
entrez
13666
canonical
uniprot
Q9Z2B5
canonical
ensembl
ENSMUSG00000031668
resolver
ensp
ENSMUSP00000034093
resolver
ensp
ENSMUSP00000123759
resolver
ensp
ENSMUSP00000311569
resolver
enst
ENSMUST00000034093
resolver
enst
ENSMUST00000162950
resolver
genesymbol
Eif2ak3
resolver
genesymbol_syn
Pek
resolver
genesymbol_syn
Perk
resolver
uniprot
A0A0R4J1Y1
resolver
uniprot
E9QQ30
resolver
uniprot
Q7TQC8
resolver
uniprot
Q9CTK8
resolver
uniprot
Q9CWT5
resolver
uniprot_entry
A0A0R4J1Y1_MOUSE
resolver
uniprot_entry
E2AK3_MOUSE
resolver
uniprot_entry
E9QQ30_MOUSE
resolver
uniprot_entry
Q7TQC8_MOUSE
resolver
uniprot_sec
Q9CTK8
resolver
uniprot_sec
Q9CWT5
resolver
activity_regulation
ACTIVITY REGULATION: Inhibited by HSPA5/BIP in absence of stress (PubMed:10854322, PubMed:11106749). 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:10854322, PubMed:11106749, PubMed:16418533, PubMed:17998206). Inactivated following phosphorylation at Thr-799 by AKT (AKT1, AKT2 and/or AKT3) (PubMed:21954288). Inhibited by ATAD3A at mitochondria-endoplasmic reticulum contact sites, providing a safe haven for mitochondrial protein translation during ER stress (By similarity). {ECO:0000250|UniProtKB:Q9NZJ5, ECO:0000269|PubMed:10854322, ECO:0000269|PubMed:11106749, ECO:0000269|PubMed:16418533, ECO:0000269|PubMed:17998206, ECO:0000269|PubMed:21954288}.
uniprot
proteins
amino_acid_sequence
MERATRPGPRALLLLLFLLLGCAAGISAVAPARSLLAPASETVFGLGAAAAPTSAARVPAVATAEVTVEDAEALPAAAGEPESRATEPDDDVELRPRGRSLVIISTLDGRIAALDAENDGKKQWDLDVGSGSLVSSSLSKPEVFGNKMIIPSLDGDLFQWDRDRESMEAVPFTVESLLESSYKFGDDVVLVGGKSLITYGLSAYSGKLRYICSALGCRRWDSDEMEEEEDILLLQRTQKTVRAVGPRSGSEKWNFSVGHFELRYIPDMETRAGFIESTFKPGGNKEDSKIISDVEEQEATMLDTVIKVSVADWKVMAFSRKGGRLEWEYQFCTPIASAWLVRDGKVIPISLFDDTSYTASEEALGDEEDIVEAARGATENSVYLGMYRGQLYLQSSVRVSEKFPTSPKALESVNGENAIIPLPTIKWKPLIHSPSRTPVLVGSDEFDKCLSNDKYSHEEYSNGALSILQYPYDNGYYLPYYKRERNKRSTQITVRFLDSPHYSKNIRKKDPILLLHWWKEIFGTILLCIVATTFIVRRLFHPQPHRQRKESETQCQTESKYDSVSADVSDNSWNDMKYSGYVSRYLTDFEPIQCMGRGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLETPPEKWQEEMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFSTKEQIEVIAPSPERSRSFSVGISCGQTSSSESQFSPLEFSGTDCGDNSDSADAAYNLQDSCLTDCEDVEDGTVDGNDEGHSFELCPSEASPYTRSREGTSSSIVFEDSGCGNASSKEEPRGNRLHDGNHYVNKLTDLKCSSSRSSSEATTLSTSPTRPTTLSLDFTKNTVGQLQPSSPKVYLYIQMQLCRKENLKDWMNRRCSLEDREHGVCLHIFLQIAEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVTAMDQDEEEQTVLTPMPAYATHTGQVGTKLYMSPEQIHGNNYSHKVDIFSLGLILFELLYPFSTQMERVRILTDVRNLKFPLLFTQKYPQEHMMVQDMLSPSPTERPEATDIIENAIFENLEFPGKTVLRQRSRSMSSSGTKHSRQPSCSYSPLPGN
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:10882126, PubMed:11106749, PubMed:11430819, PubMed:11997520, PubMed:14978030, PubMed:16418533, PubMed:17998206, PubMed:21954288, PubMed:23921556, PubMed:9930704). 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:11106749, PubMed:16418533, PubMed:17998206, PubMed:21954288, PubMed:23921556, PubMed:29386355, PubMed:9930704). 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:10882126, PubMed:11106749, PubMed:11430819, PubMed:11997520, PubMed:23921556). 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 (By similarity). 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 (PubMed:14517290, PubMed:14978030). Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1) (PubMed:11035797). Involved in control of mitochondrial morphology and function (PubMed:23921556). {ECO:0000250|UniProtKB:Q9NZJ5, ECO:0000269|PubMed:10882126, ECO:0000269|PubMed:11035797, ECO:0000269|PubMed:11106749, ECO:0000269|PubMed:11430819, ECO:0000269|PubMed:11997520, ECO:0000269|PubMed:14517290, ECO:0000269|PubMed:14978030, ECO:0000269|PubMed:16418533, ECO:0000269|PubMed:17998206, ECO:0000269|PubMed:21954288, ECO:0000269|PubMed:23921556, ECO:0000269|PubMed:29386355, ECO:0000269|PubMed:31023583, ECO:0000269|PubMed:9930704}.
uniprot
proteins
mass_dalton
124682
uniprot
proteins
mutagenesis
MUTAGEN 160; /note="W->S: Decreased binding to misfolded proteins and phosphorylation of EIF2S1/eIF-2-alpha in response to stress; when associated with 383-S--S-386."; /evidence="ECO:0000269|PubMed:29386355"; MUTAGEN 383..386; /note="YLGM->SSGS: Decreased binding to misfolded proteins and phosphorylation of EIF2S1/eIF-2-alpha in response to stress; when associated with S-160."; /evidence="ECO:0000269|PubMed:29386355"; MUTAGEN 615; /note="Y->F: Decreased ability to phosphorylate EIF2S1/eIF-2-alpha in response to stress."; /evidence="ECO:0000269|PubMed:17998206"; MUTAGEN 618; /note="K->A: Loss of protein kinase activity."; /evidence="ECO:0000269|PubMed:16418533, ECO:0000269|PubMed:17998206, ECO:0000269|PubMed:9930704"; MUTAGEN 799; /note="T->A: Abolished phosphorylation by AKT."; /evidence="ECO:0000269|PubMed:21954288
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-980 on the kinase activation loop (PubMed:16418533, PubMed:21543844, PubMed:21954288). Autophosphorylated at Tyr-615 following endoplasmic reticulum stress, leading to activate its activity (PubMed:17998206). Dephosphorylated at Tyr-615 by PTPN1/TP1B, leading to inactivate its enzyme activity (By similarity). Phosphorylation at Thr-799 by AKT (AKT1, AKT2 and/or AKT3) inactivates EIF2AK3/PERK (PubMed:21954288). {ECO:0000250|UniProtKB:Q9NZJ5, ECO:0000269|PubMed:16418533, ECO:0000269|PubMed:17998206, ECO:0000269|PubMed:21543844, ECO:0000269|PubMed:21954288}.; PTM: N-glycosylated. {ECO:0000305|PubMed:9930704}.; PTM: ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity. {ECO:0000250|UniProtKB:Q9NZJ5}.
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
10854322
uniprot
proteins
pubmed
10882126
uniprot
proteins
pubmed
11035797
uniprot
proteins
pubmed
11106749
uniprot
proteins
pubmed
11430819
uniprot
proteins
pubmed
11997520
uniprot
proteins
pubmed
12446838
uniprot
proteins
pubmed
14517290
uniprot
proteins
pubmed
14978030
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16418533
uniprot
proteins
pubmed
17998206
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
21543844
uniprot
proteins
pubmed
21954288
uniprot
proteins
pubmed
23921556
uniprot
proteins
pubmed
25925385
uniprot
proteins
pubmed
29386355
uniprot
proteins
pubmed
31023583
uniprot
proteins
pubmed
9930704
uniprot
proteins
sequence_length
1114
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:9930704}; Single-pass type I membrane protein {ECO:0000255}. Note=Localizes to the Localizes to endoplasmic reticulum membrane (PubMed:11430819). Also present at mitochondria-endoplasmic reticulum contact sites; where it interacts with ATAD3A (By similarity). {ECO:0000250|UniProtKB:Q9NZJ5, ECO:0000269|PubMed:11430819}.
uniprot
proteins
transmembrane_region
TRANSMEM 511..531; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins