Eif2ak1
entrez
27137
canonical
uniprot
Q63185
canonical
ensembl
ENSRNOG00000001050
resolver
ensp
ENSRNOP00000001392
resolver
ensp
ENSRNOP00000075036
resolver
enst
ENSRNOT00000079836
resolver
genesymbol
Eif2ak1
resolver
genesymbol_syn
Hri
resolver
uniprot
A0A0G2K9K9
resolver
uniprot
Q642C7
resolver
uniprot_entry
A0A0G2K9K9_RAT
resolver
uniprot_entry
E2AK1_RAT
resolver
uniprot_sec
Q642C7
resolver
activity_regulation
ACTIVITY REGULATION: In normal conditions, the protein kinase activity is inhibited; inhibition is relieved by various stress conditions (By similarity). 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. Inhibited by the heme metabolites biliverdin and bilirubin. Induced by oxidative stress generated by arsenite treatment. 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 (By similarity). 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:0000250|UniProtKB:Q9Z2R9}.
uniprot
proteins
amino_acid_sequence
MLGGGSVDGERDTDDDAAGAVAAPPAIDFPAEVSDPKYDESDVPAELQVFKEPLQQPTFPFLVANQLLLVSLLEHLSHVHEPNPLHSKQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHHNRAITHLMRSAKERVRQDPCQDNSYMQKIRSREIALEAQTSRYLNEFEELAILGKGGYGRVYKVRNKLDGQHYAIKKILIKSATKTDCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVLQPQDRVPIQLPSLEVLSEHEGDRNQGGVKDNESSSSIIFAELTPEKENPLAESDVKNENNNLVSYRANLVIRSSSESESSIELQEDGLNESPLRPVVKHQLPLGHSSDVEGNFTSTDESSEDNLNLLGQTEARYHLMLHIQMQLCELSLWDWIAERNNRSRECVDEAACPYVMASVATKIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACADIIQKSADWTNRNGKGTPTHTSRVGTCLYASPEQLEGSEYDAKSDMYSLGVILLELFQPFGTEMERATVLTGVRTGRIPESLSKRCPVQAKYIQLLTGRNAAQRPSALQLLQSELFQTTGNVNLTLQMKIMEQEKEIEELKKQLSLLSQDKGLKR
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. 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. 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. 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. 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. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. It thereby plays an essential protective role for RBC survival in anemias of iron deficiency. Iron deficiency also triggers activation by full-length DELE1. 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:0000250|UniProtKB:Q9Z2R9}.
uniprot
proteins
mass_dalton
69586
uniprot
proteins
post_translational_modification
PTM: Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-486 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations. {ECO:0000250|UniProtKB:Q9Z2R9}.; 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
15489334
uniprot
proteins
pubmed
20071449
uniprot
proteins
pubmed
22673903
uniprot
proteins
pubmed
32132707
uniprot
proteins
pubmed
34404736
uniprot
proteins
pubmed
7908290
uniprot
proteins
sequence_length
620
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2R9}.
uniprot
proteins