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E2AK1_RABIT
ID   E2AK1_RABIT             Reviewed;         626 AA.
AC   P33279;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1994, sequence version 1.
DT   03-AUG-2022, entry version 145.
DE   RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase 1;
DE            EC=2.7.11.1 {ECO:0000269|PubMed:3745199};
DE   AltName: Full=Heme-controlled repressor;
DE            Short=HCR;
DE   AltName: Full=Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase {ECO:0000303|PubMed:1679235};
DE   AltName: Full=Heme-regulated inhibitor {ECO:0000303|PubMed:1679235};
DE   AltName: Full=Hemin-sensitive initiation factor 2-alpha kinase;
GN   Name=EIF2AK1 {ECO:0000250|UniProtKB:Q9BQI3};
GN   Synonyms=HRI {ECO:0000303|PubMed:1679235};
OS   Oryctolagus cuniculus (Rabbit).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX   NCBI_TaxID=9986;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC   TISSUE=Reticulocyte;
RX   PubMed=1679235; DOI=10.1073/pnas.88.17.7729;
RA   Chen J.-J., Throop M.S., Gehrke L., Kuo I., Pal J.K., Brodsky M.,
RA   London I.M.;
RT   "Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2
RT   alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2
RT   protein kinase and human double-stranded-RNA-dependent eIF-2 alpha
RT   kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 88:7729-7733(1991).
RN   [2]
RP   PROTEIN SEQUENCE OF 166-178; 454-467 AND 506-525.
RC   TISSUE=Reticulocyte;
RX   PubMed=1671169; DOI=10.1073/pnas.88.2.315;
RA   Chen J.-J., Pal J.K., Petryshyn R., Kuo I., Yang J.M., Throop M.S.,
RA   Gehrke L., London I.M.;
RT   "Amino acid microsequencing of internal tryptic peptides of heme-regulated
RT   eukaryotic initiation factor 2 alpha subunit kinase: homology to protein
RT   kinases.";
RL   Proc. Natl. Acad. Sci. U.S.A. 88:315-319(1991).
RN   [3]
RP   ACTIVITY REGULATION.
RX   PubMed=2722851; DOI=10.1016/s0021-9258(18)60568-x;
RA   Chen J.J., Yang J.M., Petryshyn R., Kosower N., London I.M.;
RT   "Disulfide bond formation in the regulation of eIF-2 alpha kinase by
RT   heme.";
RL   J. Biol. Chem. 264:9559-9564(1989).
RN   [4]
RP   FUNCTION IN PHOSPHORYLATION OF EIF2S1, AND CATALYTIC ACTIVITY.
RC   TISSUE=Reticulocyte;
RX   PubMed=3745199; DOI=10.1016/s0021-9258(18)67107-8;
RA   Wettenhall R.E.H., Kudlicki W., Kramer G., Hardesty B.;
RT   "The NH2-terminal sequence of the alpha and gamma subunits of eukaryotic
RT   initiation factor 2 and the phosphorylation site for the heme-regulated
RT   eIF-2 alpha kinase.";
RL   J. Biol. Chem. 261:12444-12447(1986).
RN   [5]
RP   REVIEW.
RX   PubMed=7893826; DOI=10.1016/0300-9084(94)90080-9;
RA   Chen J.-J., Crosby J.S., London I.M.;
RT   "Regulation of heme-regulated eIF-2 alpha kinase and its expression in
RT   erythroid cells.";
RL   Biochimie 76:761-769(1994).
RN   [6]
RP   HEME-BINDING, AND MUTAGENESIS OF HIS-81 AND HIS-83.
RX   PubMed=10632719; DOI=10.1046/j.1432-1327.2000.01021.x;
RA   Uma S., Matts R.L., Guo Y., White S., Chen J.J.;
RT   "The N-terminal region of the heme-regulated eIF2alpha kinase is an
RT   autonomous heme binding domain.";
RL   Eur. J. Biochem. 267:498-506(2000).
RN   [7]
RP   MUTAGENESIS OF LYS-199, AUTOPHOSPHORYLATION, AND HEME-BINDING.
RX   PubMed=10671563; DOI=10.1074/jbc.275.7.5171;
RA   Rafie-Kolpin M., Chefalo P.J., Hussain Z., Hahn J., Uma S., Matts R.L.,
RA   Chen J.-J.;
RT   "Two heme-binding domains of heme-regulated eukaryotic initiation factor-
RT   2alpha kinase. N-terminus and kinase insertion.";
RL   J. Biol. Chem. 275:5171-5178(2000).
RN   [8]
RP   INTERACTION WITH A MULTIPROTEIN COMPLEX CONTAINING HSP90; PPP5C AND CDC37.
RX   PubMed=12022881; DOI=10.1021/bi025737a;
RA   Shao J., Hartson S.D., Matts R.L.;
RT   "Evidence that protein phosphatase 5 functions to negatively modulate the
RT   maturation of the Hsp90-dependent heme-regulated eIF2alpha kinase.";
RL   Biochemistry 41:6770-6779(2002).
RN   [9]
RP   REGULATION BY NITRIC OXIDE AND CARBON MONOXIDE.
RX   PubMed=12431098; DOI=10.1021/ja0272336;
RA   Ishikawa H., Yun B.-G., Takahashi S., Hori H., Matts R.L., Ishimori K.,
RA   Morishima I.;
RT   "NO-induced activation mechanism of the heme-regulated eIF2alpha kinase.";
RL   J. Am. Chem. Soc. 124:13696-13697(2002).
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
CC       (PubMed:3745199). Key activator of the integrated stress response (ISR)
CC       required for adaptation to various stress, such as heme deficiency,
CC       oxidative stress, osmotic shock, mitochondrial dysfunction and heat
CC       shock (By similarity). EIF2S1/eIF-2-alpha phosphorylation in response
CC       to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis
CC       inhibitor, leading to a global attenuation of cap-dependent
CC       translation, while concomitantly initiating the preferential
CC       translation of ISR-specific mRNAs, such as the transcriptional
CC       activator ATF4, and hence allowing ATF4-mediated reprogramming (By
CC       similarity). 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 (By similarity). This binding occurs with moderate affinity,
CC       allowing it to sense the heme concentration within the cell: heme
CC       depletion relieves inhibition and stimulates kinase activity,
CC       activating the ISR (By similarity). Thanks to this unique heme-sensing
CC       capacity, plays a crucial role to shut off protein synthesis during
CC       acute heme-deficient conditions (By similarity). In red blood cells
CC       (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation
CC       of the synthesis of its heme and globin moieties (By similarity). It
CC       thereby plays an essential protective role for RBC survival in anemias
CC       of iron deficiency (By similarity). Similarly, in hepatocytes, involved
CC       in heme-mediated translational control of CYP2B and CYP3A and possibly
CC       other hepatic P450 cytochromes (By similarity). May also regulate
CC       endoplasmic reticulum (ER) stress during acute heme-deficient
CC       conditions (By similarity). Also activates the ISR in response to
CC       mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is
CC       activated upon binding to the processed form of DELE1 (S-DELE1),
CC       thereby promoting the ATF4-mediated reprogramming (By similarity).
CC       {ECO:0000250|UniProtKB:Q9BQI3, ECO:0000250|UniProtKB:Q9Z2R9,
CC       ECO:0000269|PubMed:3745199}.
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:0000269|PubMed:3745199};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC         Evidence={ECO:0000269|PubMed:3745199};
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 (PubMed:2722851). 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:Q9BQI3,
CC       ECO:0000250|UniProtKB:Q9Z2R9, ECO:0000269|PubMed:2722851}.
CC   -!- SUBUNIT: Synthesized in an inactive form that binds to the N-terminal
CC       domain of CDC37 (PubMed:12022881). Has to be associated with a
CC       multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation
CC       and activation by autophosphorylation (PubMed:12022881). The
CC       phosphatase PPP5C modulates this activation (PubMed:12022881).
CC       Homodimer; homodimerizes in presence of heme, forming a disulfide-
CC       linked inactive homodimer (PubMed:2722851). Interacts with DELE1; binds
CC       to the processed form of DELE1 (S-DELE1) in response to mitochondrial
CC       stress, leading to activate its protein kinase activity and trigger the
CC       integrated stress response (ISR) (By similarity).
CC       {ECO:0000250|UniProtKB:Q9BQI3, ECO:0000269|PubMed:12022881,
CC       ECO:0000269|PubMed:2722851}.
CC   -!- INTERACTION:
CC       P33279; Q16543: CDC37; Xeno; NbExp=3; IntAct=EBI-640100, EBI-295634;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Z2R9}.
CC   -!- TISSUE SPECIFICITY: Reticulocytes. {ECO:0000269|PubMed:1679235}.
CC   -!- PTM: Activated by autophosphorylation; phosphorylated predominantly on
CC       serine and threonine residues, but also on tyrosine residues
CC       (PubMed:10671563). Autophosphorylation at Thr-483 is required for
CC       kinase activation. The active autophosphorylated form apparently is
CC       largely refractory to cellular heme fluctuations (By similarity).
CC       {ECO:0000250|UniProtKB:Q9Z2R9, ECO:0000269|PubMed:10671563}.
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; M69035; AAA31241.1; -; mRNA.
DR   PIR; A41284; A41284.
DR   RefSeq; NP_001076215.1; NM_001082746.1.
DR   AlphaFoldDB; P33279; -.
DR   SMR; P33279; -.
DR   IntAct; P33279; 3.
DR   STRING; 9986.ENSOCUP00000010856; -.
DR   GeneID; 100009522; -.
DR   KEGG; ocu:100009522; -.
DR   CTD; 27102; -.
DR   eggNOG; KOG1035; Eukaryota.
DR   InParanoid; P33279; -.
DR   OrthoDB; 64059at2759; -.
DR   Proteomes; UP000001811; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IDA:UniProtKB.
DR   GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
DR   GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0140467; P:integrated stress response signaling; ISS:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0046986; P:negative regulation of hemoglobin biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0017148; P:negative regulation of translation; IEA:UniProtKB-KW.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR   GO; GO:0006417; P:regulation of translation; NAS:UniProtKB.
DR   GO; GO:0010998; P:regulation of translational initiation by eIF2 alpha phosphorylation; IDA:UniProtKB.
DR   GO; GO:1990641; P:response to iron ion starvation; ISS:UniProtKB.
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   1: Evidence at protein level;
KW   ATP-binding; Cytoplasm; Direct protein sequencing; Disulfide bond; Kinase;
KW   Nucleotide-binding; Phosphoprotein; Protein synthesis inhibitor;
KW   Reference proteome; Repeat; Serine/threonine-protein kinase; Transferase.
FT   CHAIN           1..626
FT                   /note="Eukaryotic translation initiation factor 2-alpha
FT                   kinase 1"
FT                   /id="PRO_0000085943"
FT   DOMAIN          170..578
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REPEAT          405..410
FT                   /note="HRM 1"
FT   REPEAT          547..552
FT                   /note="HRM 2"
FT   REGION          1..37
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        437
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         176..184
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         199
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   SITE            83
FT                   /note="Heme-binding"
FT                   /evidence="ECO:0000269|PubMed:10632719"
FT   MOD_RES         481
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   MOD_RES         483
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   MOD_RES         488
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z2R9"
FT   MUTAGEN         81
FT                   /note="H->Q: No effect on heme-binding."
FT                   /evidence="ECO:0000269|PubMed:10632719"
FT   MUTAGEN         83
FT                   /note="H->Q: Strong decrease in heme-binding."
FT                   /evidence="ECO:0000269|PubMed:10632719"
FT   MUTAGEN         199
FT                   /note="K->R: Abolishes kinase activity."
FT                   /evidence="ECO:0000269|PubMed:10671563"
SQ   SEQUENCE   626 AA;  70274 MW;  4E47CC0173289B57 CRC64;
     MLGGSAGTRG GEAEGDGAGA VGAVAPPPAI DFPAEVSDPK YDESDVPAEL QVLKEPLQQP
     AFPFAVANQL LLVSLLEHLS HVHEPNPLRS RQVFKLLCQT FIKMGLLSSF TCSDEFSSLR
     LHHNRAITHL MRSARERVRQ DPCADNSHIQ KIRSREVALE AQTSRYLNEF EELSILGKGG
     YGRVYKVRNK LDGQYYAIKK ILIKGATKTD CMKVLREVKV LAGLQHPNIV GYHTAWIEHV
     HVHVQADRVP IQLPSLEVLS DQEEDRDQYG VKNDASSSSS IIFAEFSPEK EKSSDECAVE
     SQNNKLVNYT TNLVVRDTGE FESSTERQEN GSIVERQLLF GHNSDVEEDF TSAEESSEED
     LSALRHTEVQ YHLMLHIQMQ LCELSLWDWI AERNRRSREC VDESACPYVM VSVATKIFQE
     LVEGVFYIHN MGIVHRDLKP RNIFLHGPDQ QVKIGDFGLA CADIIQKNAA RTSRNGERAP
     THTSRVGTCL YASPEQLEGS EYDAKSDMYS VGVILLELFQ PFGTEMERAE VLTGVRAGRI
     PDSLSKRCPA QAKYVQLLTR RNASQRPSAL QLLQSELFQN SAHVNLTLQM KIIEQEREIE
     ELKKQLSLLS QARGVRSDRR DGELPA
 
 
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