{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9BQI3","secondaryAccessions":["A8K2R2","Q549K6","Q8NBW3","Q9HC02","Q9NYE0","Q9P0V6","Q9P1J5","Q9P2H8","Q9UHG4"],"uniProtkbId":"E2AK1_HUMAN","entryAudit":{"firstPublicDate":"2001-07-11","lastAnnotationUpdateDate":"2026-06-10","lastSequenceUpdateDate":"2003-06-20","entryVersion":218,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Eukaryotic translation initiation factor 2-alpha kinase 1"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}],"value":"2.7.11.1"}]},"alternativeNames":[{"fullName":{"value":"Heme-controlled repressor"},"shortNames":[{"value":"HCR"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.3"}],"value":"Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11101152"}],"value":"Heme-regulated inhibitor"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11101152"}],"value":"hHRI"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.2"}],"value":"Hemin-sensitive initiation factor 2-alpha kinase"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:24921"}],"value":"EIF2AK1"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11101152"}],"value":"HRI"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"10718198"}],"value":"KIAA1369"}],"orfNames":[{"value":"PRO1362"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z2R9"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132706"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32197074"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37550454"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}],"value":"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)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:17989"},{"database":"Rhea","id":"RHEA-COMP:9863"},{"database":"Rhea","id":"RHEA-COMP:11604"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:29999"},{"database":"ChEBI","id":"CHEBI:30616"},{"database":"ChEBI","id":"CHEBI:83421"},{"database":"ChEBI","id":"CHEBI:456216"}],"ecNumber":"2.7.11.1","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:17990"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:46608"},{"database":"Rhea","id":"RHEA-COMP:11060"},{"database":"Rhea","id":"RHEA-COMP:11605"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:30013"},{"database":"ChEBI","id":"CHEBI:30616"},{"database":"ChEBI","id":"CHEBI:61977"},{"database":"ChEBI","id":"CHEBI:456216"}],"ecNumber":"2.7.11.1","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z2R9"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:46609"},"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z2R9"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P33279"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z2R9"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132706"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37327776"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37550454"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}],"value":"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)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P33279"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11036079"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132706"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32132707"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37327776"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37550454"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38340717"}],"value":"Synthesized in an inactive form that binds to the N-terminal domain of CDC37 (PubMed:11036079). Has to be associated with a multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation and activation by autophosphorylation (PubMed:11036079). The phosphatase PPP5C modulates this activation (PubMed:11036079). Homodimer; homodimerizes in presence of heme, forming a disulfide-linked inactive homodimer (By similarity). Interacts with DELE1; binds both to full-length DELE1 and processed form of DELE1 (S-DELE1) in response to stress, leading to activate its protein kinase activity and trigger the integrated stress response (ISR) (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q9BQI3","intActId":"EBI-640377"},"interactantTwo":{"uniProtKBAccession":"P08238","geneName":"HSP90AB1","intActId":"EBI-352572"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9BQI3","intActId":"EBI-640377"},"interactantTwo":{"uniProtKBAccession":"P11142","geneName":"HSPA8","intActId":"EBI-351896"},"numberOfExperiments":2,"organismDiffer":false}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q9BQI3-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q9BQI3-2"],"sequenceIds":["VSP_007589"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9Z2R9"}],"value":"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"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38297121"}],"value":"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)"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome","diseaseAccession":"DI-05836","acronym":"LEMSPAD","description":"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.","diseaseCrossReference":{"database":"MIM","id":"618878"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32197074"}]},"note":{"texts":[{"value":"The disease may be caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00159"}],"value":"Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"20071449"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"34404736"}],"value":"Was reported to be expressed predominantly in erythroid cells and at much lower levels in hepatocytes. However, this paper has been retracted because there was improper manipulation, reuse and analyses"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Frameshift","sequence":"AAF70289.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAF71057.1","note":"Truncated N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAA92607.1","note":"Extended N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":630,"modifier":"EXACT"}},"description":"Eukaryotic translation initiation factor 2-alpha kinase 1","featureId":"PRO_0000085941"},{"type":"Domain","location":{"start":{"value":167,"modifier":"EXACT"},"end":{"value":583,"modifier":"EXACT"}},"description":"Protein kinase","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00159"}]},{"type":"Repeat","location":{"start":{"value":410,"modifier":"EXACT"},"end":{"value":415,"modifier":"EXACT"}},"description":"HRM 1"},{"type":"Repeat","location":{"start":{"value":552,"modifier":"EXACT"},"end":{"value":557,"modifier":"EXACT"}},"description":"HRM 2"},{"type":"Region","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":40,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Region","location":{"start":{"value":259,"modifier":"EXACT"},"end":{"value":301,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Motif","location":{"start":{"value":85,"modifier":"EXACT"},"end":{"value":104,"modifier":"EXACT"}},"description":"SIFI-degron","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"38297121"}]},{"type":"Compositional bias","location":{"start":{"value":285,"modifier":"EXACT"},"end":{"value":294,"modifier":"EXACT"}},"description":"Basic and acidic residues","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Active site","location":{"start":{"value":442,"modifier":"EXACT"},"end":{"value":442,"modifier":"EXACT"}},"description":"Proton acceptor","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00159"},{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU10027"}]},{"type":"Binding site","location":{"start":{"value":173,"modifier":"EXACT"},"end":{"value":181,"modifier":"EXACT"}},"description":"","featureCrossReferences":[{"database":"ChEBI","id":"CHEBI:30616"}],"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00159"}],"ligand":{"name":"ATP","id":"ChEBI:CHEBI:30616"}},{"type":"Binding site","location":{"start":{"value":196,"modifier":"EXACT"},"end":{"value":196,"modifier":"EXACT"}},"description":"","featureCrossReferences":[{"database":"ChEBI","id":"CHEBI:30616"}],"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00159"}],"ligand":{"name":"ATP","id":"ChEBI:CHEBI:30616"}},{"type":"Site","location":{"start":{"value":80,"modifier":"EXACT"},"end":{"value":80,"modifier":"EXACT"}},"description":"Heme-binding","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P33279"}]},{"type":"Modified residue","location":{"start":{"value":285,"modifier":"EXACT"},"end":{"value":285,"modifier":"EXACT"}},"description":"Phosphothreonine","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q63185"}]},{"type":"Modified residue","location":{"start":{"value":486,"modifier":"EXACT"},"end":{"value":486,"modifier":"EXACT"}},"description":"Phosphothreonine; 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