E2AK1_MACFA
ID E2AK1_MACFA Reviewed; 631 AA.
AC Q4R8E0;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 77.
DE RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 1 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q9Z2R9};
DE AltName: Full=Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase {ECO:0000250|UniProtKB:Q9BQI3};
DE AltName: Full=Hemin-sensitive initiation factor 2-alpha kinase {ECO:0000250|UniProtKB:Q9BQI3};
GN Name=EIF2AK1 {ECO:0000250|UniProtKB:Q9BQI3};
GN ORFNames=QtsA-12694 {ECO:0000303|Ref.1};
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RG International consortium for macaque cDNA sequencing and analysis;
RT "DNA sequences of macaque genes expressed in brain or testis and its
RT evolutionary implications.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates
CC the alpha subunit of eukaryotic translation initiation factor 2
CC (EIF2S1/eIF-2-alpha) in response to various stress conditions. Key
CC activator of the integrated stress response (ISR) required for
CC adaptation to various stress, such as heme deficiency, oxidative
CC stress, osmotic shock, mitochondrial dysfunction and heat shock.
CC EIF2S1/eIF-2-alpha phosphorylation in response to stress converts
CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to
CC a global attenuation of cap-dependent translation, while concomitantly
CC initiating the preferential translation of ISR-specific mRNAs, such as
CC the transcriptional activator ATF4, and hence allowing ATF4-mediated
CC reprogramming. Acts as a key sensor of heme-deficiency: in normal
CC conditions, binds hemin via a cysteine thiolate and histidine
CC nitrogenous coordination, leading to inhibit the protein kinase
CC activity. This binding occurs with moderate affinity, allowing it to
CC sense the heme concentration within the cell: heme depletion relieves
CC inhibition and stimulates kinase activity, activating the ISR. Thanks
CC to this unique heme-sensing capacity, plays a crucial role to shut off
CC protein synthesis during acute heme-deficient conditions. In red blood
CC cells (RBCs), controls hemoglobin synthesis ensuring a coordinated
CC regulation of the synthesis of its heme and globin moieties. It thereby
CC plays an essential protective role for RBC survival in anemias of iron
CC deficiency. Similarly, in hepatocytes, involved in heme-mediated
CC translational control of CYP2B and CYP3A and possibly other hepatic
CC P450 cytochromes. May also regulate endoplasmic reticulum (ER) stress
CC during acute heme-deficient conditions (By similarity). Also activates
CC the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein
CC kinase activity is activated upon binding to the processed form of
CC DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (By
CC similarity). {ECO:0000250|UniProtKB:Q9BQI3,
CC ECO:0000250|UniProtKB:Q9Z2R9}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2R9};
CC -!- ACTIVITY REGULATION: In normal conditions, the protein kinase activity
CC is inhibited; inhibition is relieved by various stress conditions (By
CC similarity). Inhibited by heme: in presence of heme, forms a disulfide-
CC linked inactive homodimer (By similarity). Heme depletion relieves
CC inhibition and stimulates kinase activity by autophosphorylation.
CC Inhibited by the heme metabolites biliverdin and bilirubin. Induced by
CC oxidative stress generated by arsenite treatment. Binding of nitric
CC oxide (NO) to the heme iron in the N-terminal heme-binding domain
CC activates the kinase activity, while binding of carbon monoxide (CO)
CC suppresses kinase activity (By similarity). Protein kinase activity is
CC also activated upon binding to the processed form of DELE1 (S-DELE1):
CC interaction with S-DELE1 takes place in response to mitochondrial
CC stress and triggers the integrated stress response (ISR) (By
CC similarity). {ECO:0000250|UniProtKB:P33279,
CC ECO:0000250|UniProtKB:Q9BQI3, ECO:0000250|UniProtKB:Q9Z2R9}.
CC -!- SUBUNIT: Synthesized in an inactive form that binds to the N-terminal
CC domain of CDC37. Has to be associated with a multiprotein complex
CC containing Hsp90, CDC37 and PPP5C for maturation and activation by
CC autophosphorylation. The phosphatase PPP5C modulates this activation
CC (By similarity). Homodimer; homodimerizes in presence of heme, forming
CC a disulfide-linked inactive homodimer (By similarity). Interacts with
CC DELE1; binds to the processed form of DELE1 (S-DELE1) in response to
CC mitochondrial stress, leading to activate its protein kinase activity
CC and trigger the integrated stress response (ISR) (By similarity).
CC {ECO:0000250|UniProtKB:P33279, ECO:0000250|UniProtKB:Q9BQI3}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2R9}.
CC -!- PTM: Activated by autophosphorylation; phosphorylated predominantly on
CC serine and threonine residues, but also on tyrosine residues.
CC Autophosphorylation at Thr-488 is required for kinase activation. The
CC active autophosphorylated form apparently is largely refractory to
CC cellular heme fluctuations. {ECO:0000250|UniProtKB:Q9Z2R9}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; AB168513; BAE00632.1; -; mRNA.
DR RefSeq; NP_001270717.1; NM_001283788.1.
DR AlphaFoldDB; Q4R8E0; -.
DR STRING; 9541.XP_005549148.1; -.
DR GeneID; 101865823; -.
DR CTD; 27102; -.
DR eggNOG; KOG1035; Eukaryota.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; ISS:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; IEA:UniProtKB-KW.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 2.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cytoplasm; Disulfide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Protein synthesis inhibitor; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..631
FT /note="Eukaryotic translation initiation factor 2-alpha
FT kinase 1"
FT /id="PRO_0000260275"
FT DOMAIN 167..583
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REPEAT 410..415
FT /note="HRM 1"
FT REPEAT 552..557
FT /note="HRM 2"
FT REGION 1..34
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 260..301
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 287..301
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 442
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 173..181
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 196
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 80
FT /note="Heme-binding"
FT /evidence="ECO:0000250|UniProtKB:P33279"
FT MOD_RES 285
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q63185"
FT MOD_RES 486
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT MOD_RES 488
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT MOD_RES 493
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
SQ SEQUENCE 631 AA; 71245 MW; 4AF0353747F0038A CRC64;
MQGGNSGVRK REEEGGGEGA VAAPPAIDFP AESSDLKYDE SDVPAELQVL KEPLQQPTFP
FAVANQLLLV SLLEHLSHVH EPNPLRSRQV FKLLCQTFIK MGLLSSFTCS DEFSSLRLHH
NRAITHLMRS AKERVRQDPC EDVSHIQKIR SREVAFEAQT SRYLNEFEEV AILGKGGYGR
VYKVRNKLDG QYYAIKKILI KGATKTDCMK VLREVKVLAG LQHPNIVGYH TAWIEHVHVI
QPRADRAAIE LPTLEVLSDQ EEDREQYDVK NDESSSSSIV FAEPTPEKGK RFGESDTENQ
NDKSVKYTTS LVIRDSGELE STLELQENDL AGLSTSSIME QQLPLRRNSH LDDSFTSTEE
SSEENVNFLG QTEAQYHLML HIQMQLCELS LWDWIAERNK RSRECVDESA CPYVMANVAT
KIFQELVEGV FYIHNMGIVH RDLKPRNIFL HGPDQQVKIG DFGLACTDIL QKNADWTNRN
GKRTPTHTSR VGTCLYASPE QLEGSEYDAK SDMYSLGVIL LELFQPFGTE MERAEVLTGL
RTGQLPESLS KRCPVQAKYI QHLTRRNSSQ RPSAVQLLQS ELFQTSGNVN FTLQMKIIEQ
EKEIAELKKQ LNLLSQDKGV RDDGKDGGVP V
