EIF2AK1
entrez
27102
canonical
uniprot
Q9BQI3
canonical
ensembl
ENSG00000086232
resolver
ensp
ENSP00000199389
resolver
ensp
ENSP00000528572
resolver
genesymbol
EIF2AK1
resolver
genesymbol_syn
HRI
resolver
genesymbol_syn
KIAA1369
resolver
hgnc
HGNC:24921
resolver
uniprot
A8K2R2
resolver
uniprot
Q549K6
resolver
uniprot
Q8NBW3
resolver
uniprot
Q9HC02
resolver
uniprot
Q9NYE0
resolver
uniprot
Q9P0V6
resolver
uniprot
Q9P1J5
resolver
uniprot
Q9P2H8
resolver
uniprot
Q9UHG4
resolver
uniprot_entry
E2AK1_HUMAN
resolver
uniprot_sec
A8K2R2
resolver
uniprot_sec
Q549K6
resolver
uniprot_sec
Q8NBW3
resolver
uniprot_sec
Q9HC02
resolver
uniprot_sec
Q9NYE0
resolver
uniprot_sec
Q9P0V6
resolver
uniprot_sec
Q9P1J5
resolver
uniprot_sec
Q9P2H8
resolver
uniprot_sec
Q9UHG4
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 (By similarity). 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 (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). {ECO:0000250|UniProtKB:P33279, ECO:0000250|UniProtKB:Q9Z2R9, ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:37327776, ECO:0000269|PubMed:37550454, ECO:0000269|PubMed:38340717}.
uniprot
proteins
amino_acid_sequence
MQGGNSGVRKREEEGDGAGAVAAPPAIDFPAEGPDPEYDESDVPAEIQVLKEPLQQPTFPFAVANQLLLVSLLEHLSHVHEPNPLRSRQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHHNRAITHLMRSAKERVRQDPCEDISRIQKIRSREVALEAQTSRYLNEFEELAILGKGGYGRVYKVRNKLDGQYYAIKKILIKGATKTVCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVIQPRADRAAIELPSLEVLSDQEEDREQCGVKNDESSSSSIIFAEPTPEKEKRFGESDTENQNNKSVKYTTNLVIRESGELESTLELQENGLAGLSASSIVEQQLPLRRNSHLEESFTSTEESSEENVNFLGQTEAQYHLMLHIQMQLCELSLWDWIVERNKRGREYVDESACPYVMANVATKIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACTDILQKNTDWTNRNGKRTPTHTSRVGTCLYASPEQLEGSEYDAKSDMYSLGVVLLELFQPFGTEMERAEVLTGLRTGQLPESLRKRCPVQAKYIQHLTRRNSSQRPSAIQLLQSELFQNSGNVNLTLQMKIIEQEKEIAELKKQLNLLSQDKGVRDDGKDGGVG
uniprot
proteins
disease_involvement
DISEASE: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome (LEMSPAD) [MIM:618878]: A disorder characterized by delayed motor development, speech delay with dysarthria, hypertonia, progressive spasticity, hyperreflexia, and bradykinesia. Cognition is normal. Patients manifest anxiety and attention deficit-hyperactivity disorder. {ECO:0000269|PubMed:32197074}. Note=The disease may be caused by variants affecting the gene represented in this entry.
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:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). 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:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). 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:32132706, PubMed:32132707, PubMed:37327776). 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 (By similarity). 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 (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Iron deficiency also triggers activation by full-length DELE1 (PubMed:37327776). 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 (PubMed:32132706, PubMed:32132707). 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 (PubMed:38340717). {ECO:0000250|UniProtKB:Q9Z2R9, ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:32197074, ECO:0000269|PubMed:37550454, ECO:0000269|PubMed:38340717}.
uniprot
proteins
mass_dalton
71106
uniprot
proteins
post_translational_modification
PTM: Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-488 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 (PubMed:38297121). Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1 (PubMed:38297121). {ECO:0000269|PubMed:38297121}.
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
10718198
uniprot
proteins
pubmed
10931946
uniprot
proteins
pubmed
11036079
uniprot
proteins
pubmed
11101152
uniprot
proteins
pubmed
11230166
uniprot
proteins
pubmed
12391722
uniprot
proteins
pubmed
12690205
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
20071449
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
28501589
uniprot
proteins
pubmed
32132706
uniprot
proteins
pubmed
32132707
uniprot
proteins
pubmed
32197074
uniprot
proteins
pubmed
34404736
uniprot
proteins
pubmed
37327776
uniprot
proteins
pubmed
37550454
uniprot
proteins
pubmed
38297121
uniprot
proteins
pubmed
38340717
uniprot
proteins
sequence_length
630
uniprot
proteins