Eif2ak1
entrez
15467
canonical
uniprot
Q9Z2R9
canonical
ensembl
ENSMUSG00000029613
resolver
ensp
ENSMUSP00000098056
resolver
ensp
ENSMUSP00000319359
resolver
enst
ENSMUST00000100487
resolver
genesymbol
Eif2ak1
resolver
genesymbol_syn
Hri
resolver
uniprot
Q2TA96
resolver
uniprot
Q69ZK8
resolver
uniprot
Q8C024
resolver
uniprot
Q8K123
resolver
uniprot
Q9CTP5
resolver
uniprot
Q9D601
resolver
uniprot_entry
E2AK1_MOUSE
resolver
uniprot_sec
Q2TA96
resolver
uniprot_sec
Q69ZK8
resolver
uniprot_sec
Q8C024
resolver
uniprot_sec
Q8K123
resolver
uniprot_sec
Q9CTP5
resolver
uniprot_sec
Q9D601
resolver
activity_regulation
ACTIVITY REGULATION: In normal conditions, the protein kinase activity is inhibited; inhibition is relieved by various stress conditions (PubMed:12767237, PubMed:14752110). Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer (By similarity). Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation (PubMed:12767237, PubMed:14752110). Inhibited by the heme metabolites biliverdin and bilirubin (PubMed:16893190). Induced by oxidative stress generated by arsenite treatment (PubMed:12767237). Binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity (PubMed:14752110). Protein kinase activity is also activated upon binding to DELE1 in response to various stress, triggering the integrated stress response (ISR): activated by full-length DELE1 in response to iron deficiency, while it is activated by the processed form of DELE1 (S-DELE1) in response to mitochondrial stress (By similarity). {ECO:0000250|UniProtKB:P33279, ECO:0000250|UniProtKB:Q9BQI3, ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:14752110, ECO:0000269|PubMed:16893190}.
uniprot
proteins
amino_acid_sequence
MLGGSSVDGERDTDDDAAGAVAAPPAIDFPAEVSDPKYDESDVPAELQVLKEPLQQPTFPFLVANQLLLVSLLEHLSHVHEPNPLHSKQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHHNRAITHLMRSAKERVRQDPCQDNSYMQKIRSREIAFEAQTSRYLNEFEELAILGKGGYGRVYKVRNKLDGQHYAIKKILIKSATKTDCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVVQPQDRVPIQLPSLEVLSEQEGDRDQGGVKDNESSSSIVFAELTPEKEKPFGESEVKNENNNLVSYTANLVVRNSSESESSIELQEDGLTDLSVRPVVRHQLPLGHSSELEGNFTSTDESSEGNLNLLGQTEVRYHLMLHIQMQLCELSLWDWITERNKRSREYVDEAACPYVMASVATKIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACADIIQNADWTNRNGKGTRTHTSRVGTCLYASPEQLEGSQYDAKSDMYSLGVILLELFQPFGTEMERATVLTGVRTGRIPESLSKRCPVQAKYIQLLTGRNVSQRPSALQLLQSELFQTTGNVNLTLQMKIIEQEKEIEELKKQLSLLSQDRGLKR
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 conditions (PubMed:11726526, PubMed:12767237, PubMed:16893190). Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock (PubMed:11726526, PubMed:16893190). 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 activator ATF4, and hence allowing ATF4-mediated reprogramming (PubMed:11726526, PubMed:16893190). Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (PubMed:16893190). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (PubMed:16893190). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (PubMed:16893190). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (PubMed:11050009, PubMed:11726526, PubMed:15931390). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (PubMed:11726526). Iron deficiency also triggers activation by full-length DELE1 (By similarity). Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (By similarity). Also acts as an activator of mitophagy in response to mitochondrial damage: catalyzes phosphorylation of eIF-2-alpha (EIF2S1) following activation by S-DELE1, thereby promoting mitochondrial localization of EIF2S1, triggering PRKN-independent mitophagy (By similarity). {ECO:0000250|UniProtKB:Q9BQI3, ECO:0000269|PubMed:11050009, ECO:0000269|PubMed:11726526, ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:15931390, ECO:0000269|PubMed:16893190, ECO:0000269|PubMed:20071449}.
uniprot
proteins
mass_dalton
69702
uniprot
proteins
mutagenesis
MUTAGEN 196; /note="K->R: Abolishes kinase activity. Impaired hemoglobin synthesis and proliferation of differentiating erythroid cells in knockin mice."; /evidence="ECO:0000269|PubMed:11050009, ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:9822714"; MUTAGEN 483; /note="T->A: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:12767237"; MUTAGEN 483; /note="T->D: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:12767237"; MUTAGEN 485; /note="T->A: Abolishes kinase activity."; /evidence="ECO:0000269|PubMed:12767237"; MUTAGEN 485; /note="T->D: Constitutively active kinase; loss of regulation by heme and arsenite."; /evidence="ECO:0000269|PubMed:12767237"; MUTAGEN 490; /note="T->A: Almost complete loss of kinase activity; even upon arsenite treatment."; /evidence="ECO:0000269|PubMed:12767237"; MUTAGEN 490; /note="T->D: Almost complete loss of kinase activity; even upon arsenite treatment."; /evidence="ECO:0000269|PubMed:12767237
uniprot
proteins
post_translational_modification
PTM: Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues (PubMed:11560503, PubMed:9822714). Autophosphorylation at Thr-485 is required for kinase activation (PubMed:12767237). The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations (PubMed:12767237). {ECO:0000269|PubMed:11560503, ECO:0000269|PubMed:12767237, ECO:0000269|PubMed:9822714}.; PTM: Ubiquitinated and degraded by the SIFI complex once the mitochondrial stress has been resolved, thereby providing stress response silencing. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1. {ECO:0000250|UniProtKB:Q9BQI3}.
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
11050009
uniprot
proteins
pubmed
11560503
uniprot
proteins
pubmed
11689689
uniprot
proteins
pubmed
11726526
uniprot
proteins
pubmed
12767237
uniprot
proteins
pubmed
14752110
uniprot
proteins
pubmed
15368895
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15931390
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16893190
uniprot
proteins
pubmed
17932563
uniprot
proteins
pubmed
20071449
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
34404736
uniprot
proteins
pubmed
9822714
uniprot
proteins
sequence_length
619
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11050009, ECO:0000269|PubMed:17932563}.
uniprot
proteins