Full text data of EIF2S1
EIF2S1
(EIF2A)
[Confidence: high (present in two of the MS resources)]
Eukaryotic translation initiation factor 2 subunit 1 (Eukaryotic translation initiation factor 2 subunit alpha; eIF-2-alpha; eIF-2A; eIF-2alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Eukaryotic translation initiation factor 2 subunit 1 (Eukaryotic translation initiation factor 2 subunit alpha; eIF-2-alpha; eIF-2A; eIF-2alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00219678
IPI00219678 Eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa Functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA, binds to a 40S ribosomal subunit, In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00219678 Eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa Functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA, binds to a 40S ribosomal subunit, In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P05198
ID IF2A_HUMAN Reviewed; 315 AA.
AC P05198;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Eukaryotic translation initiation factor 2 subunit 1;
DE AltName: Full=Eukaryotic translation initiation factor 2 subunit alpha;
DE Short=eIF-2-alpha;
DE Short=eIF-2A;
DE Short=eIF-2alpha;
GN Name=EIF2S1; Synonyms=EIF2A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fibroblast;
RX PubMed=2948954;
RA Ernst H., Duncan R.F., Hershey J.W.B.;
RT "Cloning and sequencing of complementary DNAs encoding the alpha-
RT subunit of translational initiation factor eIF-2. Characterization of
RT the protein and its messenger RNA.";
RL J. Biol. Chem. 262:1206-1212(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PHOSPHORYLATION STATE REGULATION BY VACCINIA VIRUS PROTEIN E3.
RX PubMed=15207627; DOI=10.1016/j.virol.2004.03.012;
RA Langland J.O., Jacobs B.L.;
RT "Inhibition of PKR by vaccinia virus: role of the N- and C-terminal
RT domains of E3L.";
RL Virology 324:419-429(2004).
RN [4]
RP INTERACTION WITH ABCF1, AND ASSOCIATION WITH RIBOSOMES.
RX PubMed=17894550; DOI=10.1042/BJ20070811;
RA Paytubi S., Morrice N.A., Boudeau J., Proud C.G.;
RT "The N-terminal region of ABC50 interacts with eukaryotic initiation
RT factor eIF2 and is a target for regulatory phosphorylation by CK2.";
RL Biochem. J. 409:223-231(2008).
RN [5]
RP PHOSPHORYLATION STATE REGULATION BY ROTAVIRUS A.
RX PubMed=18032499; DOI=10.1128/JVI.01779-07;
RA Montero H., Rojas M., Arias C.F., Lopez S.;
RT "Rotavirus infection induces the phosphorylation of eIF2alpha but
RT prevents the formation of stress granules.";
RL J. Virol. 82:1496-1504(2008).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-141, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-183.
RX PubMed=11859078; DOI=10.1074/jbc.M111804200;
RA Nonato M.C., Widom J., Clardy J.;
RT "Crystal structure of the N-terminal segment of human eukaryotic
RT translation initiation factor 2alpha.";
RL J. Biol. Chem. 277:17057-17061(2002).
RN [10]
RP STRUCTURE BY NMR OF 5-303.
RX PubMed=15341733; DOI=10.1016/j.str.2004.07.010;
RA Ito T., Marintchev A., Wagner G.;
RT "Solution structure of human initiation factor eIF2alpha reveals
RT homology to the elongation factor eEF1B.";
RL Structure 12:1693-1704(2004).
CC -!- FUNCTION: Functions in the early steps of protein synthesis by
CC forming a ternary complex with GTP and initiator tRNA. This
CC complex binds to a 40S ribosomal subunit, followed by mRNA binding
CC to form a 43S preinitiation complex. Junction of the 60S ribosomal
CC subunit to form the 80S initiation complex is preceded by
CC hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP
CC binary complex. In order for eIF-2 to recycle and catalyze another
CC round of initiation, the GDP bound to eIF-2 must exchange with GTP
CC by way of a reaction catalyzed by eIF-2B.
CC -!- SUBUNIT: Heterotrimer composed of an alpha, a beta and a gamma
CC chain. Component of an EIF2 complex at least composed of
CC CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5.
CC Interaction with METAP2 protects EIF2S1 from inhibitory
CC phosphorylation (By similarity). Interacts with ABCF1 isoform 2.
CC Associates with ribosomes.
CC -!- INTERACTION:
CC O00571:DDX3X; NbExp=3; IntAct=EBI-1056162, EBI-353779;
CC P19525:EIF2AK2; NbExp=4; IntAct=EBI-1056162, EBI-640775;
CC Q9Z2B5:Eif2ak3 (xeno); NbExp=4; IntAct=EBI-1056162, EBI-1226344;
CC P20042:EIF2S2; NbExp=6; IntAct=EBI-1056162, EBI-711977;
CC P41091:EIF2S3; NbExp=4; IntAct=EBI-1056162, EBI-1054228;
CC -!- SUBCELLULAR LOCATION: Cytoplasmic granule (By similarity).
CC Note=The cytoplasmic granules are stress granules which are a
CC dense aggregation in the cytosol composed of proteins and RNAs
CC that appear when the cell is under stress. Colocalizes with NANOS3
CC in the stress granules (By similarity).
CC -!- PTM: Substrate for at least 4 kinases: EIF2AK3/PERK, GCN2, HRI and
CC PKR. Phosphorylation stabilizes the eIF-2/GDP/eIF-2B complex and
CC prevents GDP/GTP exchange reaction, thus impairing the recycling
CC of eIF-2 between successive rounds of initiation and leading to
CC global inhibition of translation. In case of infection by vaccinia
CC virus or rotavirus A, eIF2S1 phosphorylation state is modulated.
CC -!- SIMILARITY: Belongs to the eIF-2-alpha family.
CC -!- SIMILARITY: Contains 1 S1 motif domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J02645; AAA52373.1; -; mRNA.
DR EMBL; BC002513; AAH02513.1; -; mRNA.
DR RefSeq; NP_004085.1; NM_004094.4.
DR RefSeq; XP_005267447.1; XM_005267390.1.
DR UniGene; Hs.151777; -.
DR PDB; 1KL9; X-ray; 1.90 A; A=2-183.
DR PDB; 1Q8K; NMR; -; A=5-303.
DR PDBsum; 1KL9; -.
DR PDBsum; 1Q8K; -.
DR ProteinModelPortal; P05198; -.
DR SMR; P05198; 4-303.
DR IntAct; P05198; 17.
DR MINT; MINT-2983901; -.
DR STRING; 9606.ENSP00000256383; -.
DR ChEMBL; CHEMBL1255131; -.
DR PhosphoSite; P05198; -.
DR DMDM; 124200; -.
DR OGP; P05198; -.
DR REPRODUCTION-2DPAGE; IPI00219678; -.
DR PaxDb; P05198; -.
DR PeptideAtlas; P05198; -.
DR PRIDE; P05198; -.
DR DNASU; 1965; -.
DR Ensembl; ENST00000256383; ENSP00000256383; ENSG00000134001.
DR Ensembl; ENST00000466499; ENSP00000425299; ENSG00000134001.
DR GeneID; 1965; -.
DR KEGG; hsa:1965; -.
DR UCSC; uc001xjg.3; human.
DR CTD; 1965; -.
DR GeneCards; GC14P067826; -.
DR HGNC; HGNC:3265; EIF2S1.
DR HPA; CAB011663; -.
DR MIM; 603907; gene.
DR neXtProt; NX_P05198; -.
DR PharmGKB; PA27695; -.
DR eggNOG; COG1093; -.
DR HOGENOM; HOG000199476; -.
DR HOVERGEN; HBG001910; -.
DR InParanoid; P05198; -.
DR KO; K03237; -.
DR OMA; VMVQVRQ; -.
DR OrthoDB; EOG7FZ012; -.
DR PhylomeDB; P05198; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; EIF2S1; human.
DR EvolutionaryTrace; P05198; -.
DR GeneWiki; EIF2S1; -.
DR GenomeRNAi; 1965; -.
DR NextBio; 7971; -.
DR PMAP-CutDB; P05198; -.
DR PRO; PR:P05198; -.
DR ArrayExpress; P05198; -.
DR Bgee; P05198; -.
DR CleanEx; HS_EIF2A; -.
DR CleanEx; HS_EIF2S1; -.
DR Genevestigator; P05198; -.
DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005850; C:eukaryotic translation initiation factor 2 complex; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005844; C:polysome; TAS:ProtInc.
DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB.
DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0043558; P:regulation of translational initiation in response to stress; IEA:Ensembl.
DR Gene3D; 1.10.150.190; -; 1.
DR Gene3D; 2.40.50.140; -; 1.
DR Gene3D; 3.30.70.1130; -; 1.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR003029; Rbsml_prot_S1_RNA-bd_dom.
DR InterPro; IPR022967; RNA-binding_domain_S1.
DR InterPro; IPR024055; TIF2_asu_C.
DR InterPro; IPR024054; TIF2_asu_middle.
DR InterPro; IPR011488; TIF_2_asu.
DR Pfam; PF07541; EIF_2_alpha; 1.
DR Pfam; PF00575; S1; 1.
DR SMART; SM00316; S1; 1.
DR SUPFAM; SSF110993; SSF110993; 1.
DR SUPFAM; SSF116742; SSF116742; 1.
DR SUPFAM; SSF50249; SSF50249; 1.
DR PROSITE; PS50126; S1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Initiation factor;
KW Phosphoprotein; Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT CHAIN 1 315 Eukaryotic translation initiation factor
FT 2 subunit 1.
FT /FTId=PRO_0000137382.
FT DOMAIN 17 88 S1 motif.
FT MOD_RES 49 49 Phosphoserine; by HRI (By similarity).
FT MOD_RES 52 52 Phosphoserine.
FT MOD_RES 141 141 N6-acetyllysine.
FT STRAND 8 13
FT STRAND 19 27
FT STRAND 29 36
FT TURN 37 41
FT STRAND 43 47
FT HELIX 48 50
FT TURN 60 62
FT STRAND 64 66
FT STRAND 68 77
FT TURN 78 81
FT STRAND 82 87
FT HELIX 92 118
FT HELIX 124 133
FT HELIX 135 142
FT HELIX 147 158
FT HELIX 160 163
FT HELIX 170 182
FT STRAND 190 193
FT TURN 202 204
FT HELIX 205 217
FT STRAND 218 220
FT STRAND 225 231
FT STRAND 234 240
FT HELIX 244 263
FT HELIX 282 289
FT HELIX 293 295
SQ SEQUENCE 315 AA; 36112 MW; FF3E75E3816E6B1E CRC64;
MPGLSCRFYQ HKFPEVEDVV MVNVRSIAEM GAYVSLLEYN NIEGMILLSE LSRRRIRSIN
KLIRIGRNEC VVVIRVDKEK GYIDLSKRRV SPEEAIKCED KFTKSKTVYS ILRHVAEVLE
YTKDEQLESL FQRTAWVFDD KYKRPGYGAY DAFKHAVSDP SILDSLDLNE DEREVLINNI
NRRLTPQAVK IRADIEVACY GYEGIDAVKE ALRAGLNCST ENMPIKINLI APPRYVMTTT
TLERTEGLSV LSQAMAVIKE KIEEKRGVFN VQMEPKVVTD TDETELARQM ERLERENAEV
DGDDDAEEME AKAED
//
ID IF2A_HUMAN Reviewed; 315 AA.
AC P05198;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Eukaryotic translation initiation factor 2 subunit 1;
DE AltName: Full=Eukaryotic translation initiation factor 2 subunit alpha;
DE Short=eIF-2-alpha;
DE Short=eIF-2A;
DE Short=eIF-2alpha;
GN Name=EIF2S1; Synonyms=EIF2A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fibroblast;
RX PubMed=2948954;
RA Ernst H., Duncan R.F., Hershey J.W.B.;
RT "Cloning and sequencing of complementary DNAs encoding the alpha-
RT subunit of translational initiation factor eIF-2. Characterization of
RT the protein and its messenger RNA.";
RL J. Biol. Chem. 262:1206-1212(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PHOSPHORYLATION STATE REGULATION BY VACCINIA VIRUS PROTEIN E3.
RX PubMed=15207627; DOI=10.1016/j.virol.2004.03.012;
RA Langland J.O., Jacobs B.L.;
RT "Inhibition of PKR by vaccinia virus: role of the N- and C-terminal
RT domains of E3L.";
RL Virology 324:419-429(2004).
RN [4]
RP INTERACTION WITH ABCF1, AND ASSOCIATION WITH RIBOSOMES.
RX PubMed=17894550; DOI=10.1042/BJ20070811;
RA Paytubi S., Morrice N.A., Boudeau J., Proud C.G.;
RT "The N-terminal region of ABC50 interacts with eukaryotic initiation
RT factor eIF2 and is a target for regulatory phosphorylation by CK2.";
RL Biochem. J. 409:223-231(2008).
RN [5]
RP PHOSPHORYLATION STATE REGULATION BY ROTAVIRUS A.
RX PubMed=18032499; DOI=10.1128/JVI.01779-07;
RA Montero H., Rojas M., Arias C.F., Lopez S.;
RT "Rotavirus infection induces the phosphorylation of eIF2alpha but
RT prevents the formation of stress granules.";
RL J. Virol. 82:1496-1504(2008).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-141, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-183.
RX PubMed=11859078; DOI=10.1074/jbc.M111804200;
RA Nonato M.C., Widom J., Clardy J.;
RT "Crystal structure of the N-terminal segment of human eukaryotic
RT translation initiation factor 2alpha.";
RL J. Biol. Chem. 277:17057-17061(2002).
RN [10]
RP STRUCTURE BY NMR OF 5-303.
RX PubMed=15341733; DOI=10.1016/j.str.2004.07.010;
RA Ito T., Marintchev A., Wagner G.;
RT "Solution structure of human initiation factor eIF2alpha reveals
RT homology to the elongation factor eEF1B.";
RL Structure 12:1693-1704(2004).
CC -!- FUNCTION: Functions in the early steps of protein synthesis by
CC forming a ternary complex with GTP and initiator tRNA. This
CC complex binds to a 40S ribosomal subunit, followed by mRNA binding
CC to form a 43S preinitiation complex. Junction of the 60S ribosomal
CC subunit to form the 80S initiation complex is preceded by
CC hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP
CC binary complex. In order for eIF-2 to recycle and catalyze another
CC round of initiation, the GDP bound to eIF-2 must exchange with GTP
CC by way of a reaction catalyzed by eIF-2B.
CC -!- SUBUNIT: Heterotrimer composed of an alpha, a beta and a gamma
CC chain. Component of an EIF2 complex at least composed of
CC CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5.
CC Interaction with METAP2 protects EIF2S1 from inhibitory
CC phosphorylation (By similarity). Interacts with ABCF1 isoform 2.
CC Associates with ribosomes.
CC -!- INTERACTION:
CC O00571:DDX3X; NbExp=3; IntAct=EBI-1056162, EBI-353779;
CC P19525:EIF2AK2; NbExp=4; IntAct=EBI-1056162, EBI-640775;
CC Q9Z2B5:Eif2ak3 (xeno); NbExp=4; IntAct=EBI-1056162, EBI-1226344;
CC P20042:EIF2S2; NbExp=6; IntAct=EBI-1056162, EBI-711977;
CC P41091:EIF2S3; NbExp=4; IntAct=EBI-1056162, EBI-1054228;
CC -!- SUBCELLULAR LOCATION: Cytoplasmic granule (By similarity).
CC Note=The cytoplasmic granules are stress granules which are a
CC dense aggregation in the cytosol composed of proteins and RNAs
CC that appear when the cell is under stress. Colocalizes with NANOS3
CC in the stress granules (By similarity).
CC -!- PTM: Substrate for at least 4 kinases: EIF2AK3/PERK, GCN2, HRI and
CC PKR. Phosphorylation stabilizes the eIF-2/GDP/eIF-2B complex and
CC prevents GDP/GTP exchange reaction, thus impairing the recycling
CC of eIF-2 between successive rounds of initiation and leading to
CC global inhibition of translation. In case of infection by vaccinia
CC virus or rotavirus A, eIF2S1 phosphorylation state is modulated.
CC -!- SIMILARITY: Belongs to the eIF-2-alpha family.
CC -!- SIMILARITY: Contains 1 S1 motif domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J02645; AAA52373.1; -; mRNA.
DR EMBL; BC002513; AAH02513.1; -; mRNA.
DR RefSeq; NP_004085.1; NM_004094.4.
DR RefSeq; XP_005267447.1; XM_005267390.1.
DR UniGene; Hs.151777; -.
DR PDB; 1KL9; X-ray; 1.90 A; A=2-183.
DR PDB; 1Q8K; NMR; -; A=5-303.
DR PDBsum; 1KL9; -.
DR PDBsum; 1Q8K; -.
DR ProteinModelPortal; P05198; -.
DR SMR; P05198; 4-303.
DR IntAct; P05198; 17.
DR MINT; MINT-2983901; -.
DR STRING; 9606.ENSP00000256383; -.
DR ChEMBL; CHEMBL1255131; -.
DR PhosphoSite; P05198; -.
DR DMDM; 124200; -.
DR OGP; P05198; -.
DR REPRODUCTION-2DPAGE; IPI00219678; -.
DR PaxDb; P05198; -.
DR PeptideAtlas; P05198; -.
DR PRIDE; P05198; -.
DR DNASU; 1965; -.
DR Ensembl; ENST00000256383; ENSP00000256383; ENSG00000134001.
DR Ensembl; ENST00000466499; ENSP00000425299; ENSG00000134001.
DR GeneID; 1965; -.
DR KEGG; hsa:1965; -.
DR UCSC; uc001xjg.3; human.
DR CTD; 1965; -.
DR GeneCards; GC14P067826; -.
DR HGNC; HGNC:3265; EIF2S1.
DR HPA; CAB011663; -.
DR MIM; 603907; gene.
DR neXtProt; NX_P05198; -.
DR PharmGKB; PA27695; -.
DR eggNOG; COG1093; -.
DR HOGENOM; HOG000199476; -.
DR HOVERGEN; HBG001910; -.
DR InParanoid; P05198; -.
DR KO; K03237; -.
DR OMA; VMVQVRQ; -.
DR OrthoDB; EOG7FZ012; -.
DR PhylomeDB; P05198; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; EIF2S1; human.
DR EvolutionaryTrace; P05198; -.
DR GeneWiki; EIF2S1; -.
DR GenomeRNAi; 1965; -.
DR NextBio; 7971; -.
DR PMAP-CutDB; P05198; -.
DR PRO; PR:P05198; -.
DR ArrayExpress; P05198; -.
DR Bgee; P05198; -.
DR CleanEx; HS_EIF2A; -.
DR CleanEx; HS_EIF2S1; -.
DR Genevestigator; P05198; -.
DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005850; C:eukaryotic translation initiation factor 2 complex; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005844; C:polysome; TAS:ProtInc.
DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB.
DR GO; GO:0003743; F:translation initiation factor activity; IDA:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0043558; P:regulation of translational initiation in response to stress; IEA:Ensembl.
DR Gene3D; 1.10.150.190; -; 1.
DR Gene3D; 2.40.50.140; -; 1.
DR Gene3D; 3.30.70.1130; -; 1.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR003029; Rbsml_prot_S1_RNA-bd_dom.
DR InterPro; IPR022967; RNA-binding_domain_S1.
DR InterPro; IPR024055; TIF2_asu_C.
DR InterPro; IPR024054; TIF2_asu_middle.
DR InterPro; IPR011488; TIF_2_asu.
DR Pfam; PF07541; EIF_2_alpha; 1.
DR Pfam; PF00575; S1; 1.
DR SMART; SM00316; S1; 1.
DR SUPFAM; SSF110993; SSF110993; 1.
DR SUPFAM; SSF116742; SSF116742; 1.
DR SUPFAM; SSF50249; SSF50249; 1.
DR PROSITE; PS50126; S1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Initiation factor;
KW Phosphoprotein; Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT CHAIN 1 315 Eukaryotic translation initiation factor
FT 2 subunit 1.
FT /FTId=PRO_0000137382.
FT DOMAIN 17 88 S1 motif.
FT MOD_RES 49 49 Phosphoserine; by HRI (By similarity).
FT MOD_RES 52 52 Phosphoserine.
FT MOD_RES 141 141 N6-acetyllysine.
FT STRAND 8 13
FT STRAND 19 27
FT STRAND 29 36
FT TURN 37 41
FT STRAND 43 47
FT HELIX 48 50
FT TURN 60 62
FT STRAND 64 66
FT STRAND 68 77
FT TURN 78 81
FT STRAND 82 87
FT HELIX 92 118
FT HELIX 124 133
FT HELIX 135 142
FT HELIX 147 158
FT HELIX 160 163
FT HELIX 170 182
FT STRAND 190 193
FT TURN 202 204
FT HELIX 205 217
FT STRAND 218 220
FT STRAND 225 231
FT STRAND 234 240
FT HELIX 244 263
FT HELIX 282 289
FT HELIX 293 295
SQ SEQUENCE 315 AA; 36112 MW; FF3E75E3816E6B1E CRC64;
MPGLSCRFYQ HKFPEVEDVV MVNVRSIAEM GAYVSLLEYN NIEGMILLSE LSRRRIRSIN
KLIRIGRNEC VVVIRVDKEK GYIDLSKRRV SPEEAIKCED KFTKSKTVYS ILRHVAEVLE
YTKDEQLESL FQRTAWVFDD KYKRPGYGAY DAFKHAVSDP SILDSLDLNE DEREVLINNI
NRRLTPQAVK IRADIEVACY GYEGIDAVKE ALRAGLNCST ENMPIKINLI APPRYVMTTT
TLERTEGLSV LSQAMAVIKE KIEEKRGVFN VQMEPKVVTD TDETELARQM ERLERENAEV
DGDDDAEEME AKAED
//
MIM
603907
*RECORD*
*FIELD* NO
603907
*FIELD* TI
*603907 EUKARYOTIC TRANSLATION INITIATION FACTOR 2, SUBUNIT 1; EIF2S1
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA;;
read moreEIF2-ALPHA
*FIELD* TX
DESCRIPTION
The translation initiation factor EIF2 catalyzes the first regulated
step of protein synthesis initiation, promoting the binding of the
initiator tRNA to 40S ribosomal subunits. Binding occurs as a ternary
complex of methionyl-tRNA, EIF2, and GTP. EIF2 is composed of 3
nonidentical subunits, the 36-kD EIF2-alpha subunit (EIF2S1), the 38-kD
EIF2-beta subunit (EIF2S2; 603908), and the 52-kD EIF2-gamma subunit
(EIF2S3; 300161). The rate of formation of the ternary complex is
modulated by the phosphorylation state of EIF2-alpha (Ernst et al.,
1987).
CLONING
By screening a rat brain expression library with antibodies against
human EIF2S1, which they called EIF2-alpha, Ernst et al. (1987) isolated
cDNAs encoding rat Eif2-alpha. They used a rat cDNA to screen a human
fibroblast library and recovered a human EIF2-alpha cDNA. The predicted
315-amino acid human and rat proteins differ at only 3 residues and are
likely processed posttranslationally by removal of their N-terminal
methionines. Northern blot analysis detected a 1.6-kb EIF2-alpha mRNA in
HeLa cells.
NOMENCLATURE
EIF2-alpha should not be confused with EIF2A (609234), a distinct
translation initiation factor.
GENE FUNCTION
Ernst et al. (1987) stated that protein synthesis is inhibited due to
phosphorylation of Eif2-alpha in hemin-deprived rabbit reticulocyte
lysates. HeLa cells subjected to heat shock, serum deprivation, or
interferon treatment followed by virus infection also show a correlation
between EIF2-alpha phosphorylation and translational repression. EIF2
must associate with EIF2B (see 606686) to function catalytically, and
phosphorylation of EIF2-alpha results in formation of irreversible
inactive complexes with EIF2B, thereby preventing mRNA translation.
Ernst et al. (1987) found that the decrease of EIF2-alpha protein
synthesis in serum-depleted HeLa cells appeared to be due to specific
modulation of the rate of translation initiation of existing EIF2-alpha
mRNA.
Using site-directed mutagenesis, in vitro translation, and 2-dimensional
gel electrophoresis, Pathak et al. (1988) identified ser51 in the mature
human EIF2-alpha protein as the sole site of phosphorylation leading to
repression of protein synthesis.
Jacob et al. (1989) found that the alpha-Pal (NRF1; 600879)
transcription factor bound to 2 palindromic sites within the EIF2-alpha
promoter and was essential for transcription of the EIF2-alpha gene.
Noguchi et al. (1994) identified an EIF2-alpha antisense transcript in
vivo and found that it appeared to modulate EIF2-alpha gene expression.
Upon brain reperfusion following ischemia, there is widespread
inhibition of neuronal protein synthesis due to phosphorylation of
Eif2-alpha, which persists in vulnerable neurons destined to undergo
apoptosis. Page et al. (2003) examined rat CA1 pyramidal neurons at 4
hours of reperfusion following 10-minute cardiac arrest and found
complete colocalization between phosphorylated Eif2-alpha and cytosolic
cytochrome c (see 516030), which is released from mitochondria early in
apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c
release, suggesting that phosphorylation of Eif2-alpha is upstream of
cytochrome c release during apoptotic cell death.
Blais et al. (2004) determined that EIF2-alpha, PERK (EIF2AK3; 604032),
ATF4 (604064), and GADD34 (PPP1R15A; 611048) are involved in an
integrated adaptive response to hypoxic stress in HeLa cells.
GTP hydrolysis by EIF2 is a critical step in translation initiation in
eukaryotes because it appears to commit the translation machinery to
assembling the ribosomal complex on the RNA start codon. Using a
reconstituted yeast translation initiation system, Algire et al. (2005)
found that GTP hydrolysis by Eif2 was enhanced by a structural
rearrangement in the 43S complex. The release of inorganic phosphate
from Eif2 was dependent on the presence of an AUG codon in the mRNA, and
Eif1 release from the 43S-mRNA complex regulated the release of
inorganic phosphate from Eif2.
In a screen for small molecules that could protect rat pheochromocytoma
cells from endoplasmic reticulum stress, Boyce et al. (2005) identified
salubrinal, a selective inhibitor of cellular complexes that
dephosphorylate Eif2-alpha. Salubrinal also blocked Eif2-alpha
dephosphorylation mediated by a herpes simplex virus protein and
inhibited viral replication. EIF2-alpha phosphorylation is
cytoprotective during endoplasmic reticulum stress, because cells are
sensitized when this pathway is genetically ablated (Harding et al.,
2000; Scheuner et al., 2001) and protected when it is ectopically
enforced (Jousse et al., 2003; Lu et al., 2004).
Using mice with mutations in Eif2-alpha, Ppp1r15a (611048), and/or
Ppp1r15b (613257), Harding et al. (2009) showed that Eif2-alpha has an
essential role in erythropoiesis and that Ppp1r15a and Ppp1r15b regulate
Eif2-alpha activity by promoting dephosphorylation of ser51.
One arm of the unfolded protein response results in the transient
shutdown of protein translation, through phosphorylation of the
alpha-subunit of eIF2. Activation of the unfolded protein response
and/or increased eIF2-alpha protein levels are seen in patients with
Alzheimer (104300), Parkinson (168600), and prion diseases, but how this
relates to neurodegeneration was unknown. Moreno et al. (2012) showed
that accumulation of prion protein during prion replication caused
persistent translational repression of global protein synthesis by
eIF2-alpha, associated with synaptic failure and neuronal loss in
prion-diseased mice. Further, Moreno et al. (2012) showed that promoting
translational recovery in hippocampi of prion-infected mice was
neuroprotective. Overexpression of GADD34 (PPP1R15A), a specific
eIF2-alpha protein phosphatase, as well as reduction of levels of prion
protein by lentivirally mediated RNA interference, reduced eIF2-alpha
protein levels. As a result, both approaches restored vital translation
rates during prion disease, rescuing synaptic deficits and neuronal
loss, thereby significantly increasing survival. In contrast,
salubrinal, an inhibitor of eIF2-alpha protein dephosphorylation,
increased eIF2-alpha protein levels, exacerbating neurotoxicity and
significantly reducing survival in prion-diseased mice. Given the
prevalence of protein misfolding and activation of the unfolded protein
response in several neurodegenerative diseases, Moreno et al. (2012)
concluded that manipulation of common pathways such as translational
control, rather than disease-specific approaches, may lead to therapies
preventing synaptic failure and neuronal loss across the spectrum of
these disorders.
GENE STRUCTURE
Humbelin et al. (1989) characterized the promoter region and genomic
organization of the EIF2-alpha gene. They reported that the gene spans
less than 30 kb and contains at least 4 exons.
MAPPING
Hartz (2010) mapped the EIF2S1 gene to chromosome 14q23.3 based on an
alignment of the EIF2S1 sequence (GenBank GENBANK J02645) with the
genomic sequence (GRCh37).
ANIMAL MODEL
The accumulation of unfolded protein in the endoplasmic reticulum (ER)
attenuates protein synthesis initiation through phosphorylation of the
mature EIF2-alpha protein at ser51. Subsequently, transcription of genes
encoding adaptive functions, including glucose-regulated proteins, is
induced. Scheuner et al. (2001) showed that Eif2-alpha phosphorylation
was required for translation attenuation, transcriptional induction, and
survival in response to ER stress in mice. Mice with a homozygous
mutation (ser51 to ala; S51A) at the Eif2-alpha phosphorylation site
died within 18 hours after birth due to hypoglycemia associated with
defective gluconeogenesis. In addition, homozygous mutant embryos and
neonates displayed a deficiency in pancreatic beta cells. The results
demonstrated that regulation of translation through Eif2-alpha
phosphorylation is essential for the ER stress response and in vivo
glucose homeostasis. Scheuner et al. (2005) showed that mice
heterozygous for the ser51-to-ala substitution became obese and diabetic
on a high-fat diet. Profound glucose intolerance resulted from reduced
insulin secretion accompanied by abnormal distention of the ER lumen,
defective trafficking of proinsulin, and a reduced number of insulin
granules in beta cells. Scheuner et al. (2005) proposed that
translational control couples insulin synthesis with folding capacity to
maintain ER integrity and that this signal is essential to prevent
diet-induced type II diabetes.
*FIELD* RF
1. Algire, M. A.; Maag, D.; Lorsch, J. R.: P(i) release from eIF2,
not GTP hydrolysis, is the step controlled by start-site selection
during eukaryotic translation initiation. Molec. Cell 20: 251-262,
2005.
2. Blais, J. D.; Filipenko, V.; Bi, M.; Harding, H. P.; Ron, D.; Koumenis,
C.; Wouters, B. G.; Bell, J. C.: Activating transcription factor
4 is translationally regulated by hypoxic stress. Molec. Cell. Biol. 24:
7469-7482, 2004.
3. Boyce, M.; Bryant, K. F.; Jousse, C.; Long, K.; Harding, H. P.;
Scheuner, D.; Kaufman, R. J.; Ma, D.; Coen, D. M.; Ron, D.; Yuan,
Y.: A selective inhibitor of elF2-alpha dephosphorylation protects
cells from ER stress. Science 307: 935-939, 2005.
4. Ernst, H.; Duncan, R. F.; Hershey, J. W. B.: Cloning and sequencing
of complementary DNAs encoding the alpha-subunit of translational
initiation factor eIF-2: characterization of the protein and its messenger
RNA. J. Biol. Chem. 262: 1206-1212, 1987.
5. Harding, H. P.; Zhang, Y.; Bertolotti, A.; Zeng, H.; Ron, D.:
Perk is essential for translational regulation and cell survival during
the unfolded protein response. Molec. Cell 5: 897-904, 2000.
6. Harding, H. P.; Zhang, Y.; Scheuner, D.; Chen, J.-J.; Kaufman,
R. J.; Ron, D.: Ppp1r15 gene knockout reveals an essential role for
translation initiation factor 2 alpha (eIF2-alpha) dephosphorylation
in mammalian development. Proc. Nat. Acad. Sci. 106: 1832-1837,
2009.
7. Hartz, P. A.: Personal Communication. Baltimore, Md. 1/28/2010.
8. Humbelin, M.; Safer, B.; Chiorini, J. A.; Hershey, J. W. B.; Cohen,
R. B.: Isolation and characterization of the promoter and flanking
regions of the gene encoding the human protein-synthesis-initiation
factor 2-alpha. Gene 81: 315-324, 1989.
9. Jacob, W. F.; Silverman, T. A.; Cohen, R. B.; Safer, B.: Identification
and characterization of a novel transcription factor participating
in the expression of eukaryotic initiation factor 2 alpha. J. Biol.
Chem. 264: 20372-20384, 1989.
10. Jousse, C.; Oyadomari, S.; Novoa, I.; Lu, P.; Zhang, Y.; Harding,
H. P.; Ron, D.: Inhibition of a constitutive translation initiation
factor 2-alpha phosphatase, CReP, promotes survival of stressed cells. J.
Cell Biol. 163: 767-775, 2003.
11. Lu, P. D.; Jousse, C.; Marciniak, S. J.; Zhang, Y.; Novoa, I.;
Scheuner, D.; Kaufman, R. J.; Ron, D.; Harding, H. P.: Cytoprotection
by pre-emptive conditional phosphorylation of translation initiation
factor 2. EMBO J. 23: 169-179, 2004.
12. Moreno, J. A.; Radford, H.; Peretti, D.; Steinert, J. R.; Verity,
N.; Martin, M. G.; Halliday, M.; Morgan, J.; Dinsdale, D.; Ortori,
C. A.; Barrett, D. A.; Tsaytler, P.; Bertolotti, A.; Willis, A. E.;
Bushell, M.; Mallucci, G. R.: Sustained translational repression
by eIF2-alpha-P mediates prion neurodegeneration. Nature 485: 507-511,
2012.
13. Noguchi, M.; Miyamoto, S.; Silverman, T. A.; Safer, B.: Characterization
of an antisense Inr element in the eIF-2-alpha gene. J. Biol. Chem. 269:
29161-29167, 1994.
14. Page, A. B.; Owen, C. R.; Kumar, R.; Miller, J. M.; Rafols, J.
A.; White, B. C.; DeGracia, D. J.; Krause, G. S.: Persistent eIF2-alpha(P)
is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal
neurons after 4 hours of reperfusion following 10-minute complete
brain ischemia. Acta Neuropath. 106: 8-16, 2003.
15. Pathak, V. K.; Schindler, D.; Hershey, J. W. B.: Generation of
a mutant form of protein synthesis initiation factor eIF-2 lacking
the site of phosphorylation by eIF-2 kinases. Molec. Cell. Biol. 8:
993-995, 1988.
16. Scheuner, D.; Song, B.; McEwen, E.; Liu, C.; Laybutt, R.; Gillespie,
P.; Saunders, T.; Bonner-Weir, S.; Kaufman, R. J.: Translational
control is required for the unfolded protein response and in vivo
glucose homeostasis. Molec. Cell 7: 1165-1176, 2001.
17. Scheuner, D.; Vander Mierde, D.; Song, B.; Flamez, D.; Creemers,
J. W. M.; Tsukamoto, K.; Ribick, M.; Schuit, F. C.; Kaufman, R. J.
: Control of mRNA translation preserves endoplasmic reticulum function
in beta cells and maintains glucose homeostasis. Nature Med. 11:
757-764, 2005.
*FIELD* CN
Ada Hamosh - updated: 10/19/2012
Patricia A. Hartz - updated: 2/19/2010
Patricia A. Hartz - updated: 1/28/2010
Ada Hamosh - updated: 2/10/2006
Patricia A. Hartz - updated: 11/22/2005
Marla J. F. O'Neill - updated: 7/27/2005
Patricia A. Hartz - updated: 3/3/2005
Patricia A. Hartz - updated: 9/23/2004
Stylianos E. Antonarakis - updated: 7/3/2001
*FIELD* CD
Rebekah S. Rasooly: 6/15/1999
*FIELD* ED
alopez: 10/19/2012
mgross: 2/19/2010
terry: 2/19/2010
mgross: 2/4/2010
mgross: 2/1/2010
terry: 1/28/2010
mgross: 5/21/2007
terry: 11/3/2006
alopez: 2/17/2006
terry: 2/10/2006
wwang: 11/29/2005
terry: 11/22/2005
terry: 10/4/2005
wwang: 8/3/2005
terry: 7/27/2005
mgross: 3/3/2005
mgross: 9/23/2004
mgross: 7/3/2001
alopez: 7/20/1999
alopez: 6/16/1999
*RECORD*
*FIELD* NO
603907
*FIELD* TI
*603907 EUKARYOTIC TRANSLATION INITIATION FACTOR 2, SUBUNIT 1; EIF2S1
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA;;
read moreEIF2-ALPHA
*FIELD* TX
DESCRIPTION
The translation initiation factor EIF2 catalyzes the first regulated
step of protein synthesis initiation, promoting the binding of the
initiator tRNA to 40S ribosomal subunits. Binding occurs as a ternary
complex of methionyl-tRNA, EIF2, and GTP. EIF2 is composed of 3
nonidentical subunits, the 36-kD EIF2-alpha subunit (EIF2S1), the 38-kD
EIF2-beta subunit (EIF2S2; 603908), and the 52-kD EIF2-gamma subunit
(EIF2S3; 300161). The rate of formation of the ternary complex is
modulated by the phosphorylation state of EIF2-alpha (Ernst et al.,
1987).
CLONING
By screening a rat brain expression library with antibodies against
human EIF2S1, which they called EIF2-alpha, Ernst et al. (1987) isolated
cDNAs encoding rat Eif2-alpha. They used a rat cDNA to screen a human
fibroblast library and recovered a human EIF2-alpha cDNA. The predicted
315-amino acid human and rat proteins differ at only 3 residues and are
likely processed posttranslationally by removal of their N-terminal
methionines. Northern blot analysis detected a 1.6-kb EIF2-alpha mRNA in
HeLa cells.
NOMENCLATURE
EIF2-alpha should not be confused with EIF2A (609234), a distinct
translation initiation factor.
GENE FUNCTION
Ernst et al. (1987) stated that protein synthesis is inhibited due to
phosphorylation of Eif2-alpha in hemin-deprived rabbit reticulocyte
lysates. HeLa cells subjected to heat shock, serum deprivation, or
interferon treatment followed by virus infection also show a correlation
between EIF2-alpha phosphorylation and translational repression. EIF2
must associate with EIF2B (see 606686) to function catalytically, and
phosphorylation of EIF2-alpha results in formation of irreversible
inactive complexes with EIF2B, thereby preventing mRNA translation.
Ernst et al. (1987) found that the decrease of EIF2-alpha protein
synthesis in serum-depleted HeLa cells appeared to be due to specific
modulation of the rate of translation initiation of existing EIF2-alpha
mRNA.
Using site-directed mutagenesis, in vitro translation, and 2-dimensional
gel electrophoresis, Pathak et al. (1988) identified ser51 in the mature
human EIF2-alpha protein as the sole site of phosphorylation leading to
repression of protein synthesis.
Jacob et al. (1989) found that the alpha-Pal (NRF1; 600879)
transcription factor bound to 2 palindromic sites within the EIF2-alpha
promoter and was essential for transcription of the EIF2-alpha gene.
Noguchi et al. (1994) identified an EIF2-alpha antisense transcript in
vivo and found that it appeared to modulate EIF2-alpha gene expression.
Upon brain reperfusion following ischemia, there is widespread
inhibition of neuronal protein synthesis due to phosphorylation of
Eif2-alpha, which persists in vulnerable neurons destined to undergo
apoptosis. Page et al. (2003) examined rat CA1 pyramidal neurons at 4
hours of reperfusion following 10-minute cardiac arrest and found
complete colocalization between phosphorylated Eif2-alpha and cytosolic
cytochrome c (see 516030), which is released from mitochondria early in
apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c
release, suggesting that phosphorylation of Eif2-alpha is upstream of
cytochrome c release during apoptotic cell death.
Blais et al. (2004) determined that EIF2-alpha, PERK (EIF2AK3; 604032),
ATF4 (604064), and GADD34 (PPP1R15A; 611048) are involved in an
integrated adaptive response to hypoxic stress in HeLa cells.
GTP hydrolysis by EIF2 is a critical step in translation initiation in
eukaryotes because it appears to commit the translation machinery to
assembling the ribosomal complex on the RNA start codon. Using a
reconstituted yeast translation initiation system, Algire et al. (2005)
found that GTP hydrolysis by Eif2 was enhanced by a structural
rearrangement in the 43S complex. The release of inorganic phosphate
from Eif2 was dependent on the presence of an AUG codon in the mRNA, and
Eif1 release from the 43S-mRNA complex regulated the release of
inorganic phosphate from Eif2.
In a screen for small molecules that could protect rat pheochromocytoma
cells from endoplasmic reticulum stress, Boyce et al. (2005) identified
salubrinal, a selective inhibitor of cellular complexes that
dephosphorylate Eif2-alpha. Salubrinal also blocked Eif2-alpha
dephosphorylation mediated by a herpes simplex virus protein and
inhibited viral replication. EIF2-alpha phosphorylation is
cytoprotective during endoplasmic reticulum stress, because cells are
sensitized when this pathway is genetically ablated (Harding et al.,
2000; Scheuner et al., 2001) and protected when it is ectopically
enforced (Jousse et al., 2003; Lu et al., 2004).
Using mice with mutations in Eif2-alpha, Ppp1r15a (611048), and/or
Ppp1r15b (613257), Harding et al. (2009) showed that Eif2-alpha has an
essential role in erythropoiesis and that Ppp1r15a and Ppp1r15b regulate
Eif2-alpha activity by promoting dephosphorylation of ser51.
One arm of the unfolded protein response results in the transient
shutdown of protein translation, through phosphorylation of the
alpha-subunit of eIF2. Activation of the unfolded protein response
and/or increased eIF2-alpha protein levels are seen in patients with
Alzheimer (104300), Parkinson (168600), and prion diseases, but how this
relates to neurodegeneration was unknown. Moreno et al. (2012) showed
that accumulation of prion protein during prion replication caused
persistent translational repression of global protein synthesis by
eIF2-alpha, associated with synaptic failure and neuronal loss in
prion-diseased mice. Further, Moreno et al. (2012) showed that promoting
translational recovery in hippocampi of prion-infected mice was
neuroprotective. Overexpression of GADD34 (PPP1R15A), a specific
eIF2-alpha protein phosphatase, as well as reduction of levels of prion
protein by lentivirally mediated RNA interference, reduced eIF2-alpha
protein levels. As a result, both approaches restored vital translation
rates during prion disease, rescuing synaptic deficits and neuronal
loss, thereby significantly increasing survival. In contrast,
salubrinal, an inhibitor of eIF2-alpha protein dephosphorylation,
increased eIF2-alpha protein levels, exacerbating neurotoxicity and
significantly reducing survival in prion-diseased mice. Given the
prevalence of protein misfolding and activation of the unfolded protein
response in several neurodegenerative diseases, Moreno et al. (2012)
concluded that manipulation of common pathways such as translational
control, rather than disease-specific approaches, may lead to therapies
preventing synaptic failure and neuronal loss across the spectrum of
these disorders.
GENE STRUCTURE
Humbelin et al. (1989) characterized the promoter region and genomic
organization of the EIF2-alpha gene. They reported that the gene spans
less than 30 kb and contains at least 4 exons.
MAPPING
Hartz (2010) mapped the EIF2S1 gene to chromosome 14q23.3 based on an
alignment of the EIF2S1 sequence (GenBank GENBANK J02645) with the
genomic sequence (GRCh37).
ANIMAL MODEL
The accumulation of unfolded protein in the endoplasmic reticulum (ER)
attenuates protein synthesis initiation through phosphorylation of the
mature EIF2-alpha protein at ser51. Subsequently, transcription of genes
encoding adaptive functions, including glucose-regulated proteins, is
induced. Scheuner et al. (2001) showed that Eif2-alpha phosphorylation
was required for translation attenuation, transcriptional induction, and
survival in response to ER stress in mice. Mice with a homozygous
mutation (ser51 to ala; S51A) at the Eif2-alpha phosphorylation site
died within 18 hours after birth due to hypoglycemia associated with
defective gluconeogenesis. In addition, homozygous mutant embryos and
neonates displayed a deficiency in pancreatic beta cells. The results
demonstrated that regulation of translation through Eif2-alpha
phosphorylation is essential for the ER stress response and in vivo
glucose homeostasis. Scheuner et al. (2005) showed that mice
heterozygous for the ser51-to-ala substitution became obese and diabetic
on a high-fat diet. Profound glucose intolerance resulted from reduced
insulin secretion accompanied by abnormal distention of the ER lumen,
defective trafficking of proinsulin, and a reduced number of insulin
granules in beta cells. Scheuner et al. (2005) proposed that
translational control couples insulin synthesis with folding capacity to
maintain ER integrity and that this signal is essential to prevent
diet-induced type II diabetes.
*FIELD* RF
1. Algire, M. A.; Maag, D.; Lorsch, J. R.: P(i) release from eIF2,
not GTP hydrolysis, is the step controlled by start-site selection
during eukaryotic translation initiation. Molec. Cell 20: 251-262,
2005.
2. Blais, J. D.; Filipenko, V.; Bi, M.; Harding, H. P.; Ron, D.; Koumenis,
C.; Wouters, B. G.; Bell, J. C.: Activating transcription factor
4 is translationally regulated by hypoxic stress. Molec. Cell. Biol. 24:
7469-7482, 2004.
3. Boyce, M.; Bryant, K. F.; Jousse, C.; Long, K.; Harding, H. P.;
Scheuner, D.; Kaufman, R. J.; Ma, D.; Coen, D. M.; Ron, D.; Yuan,
Y.: A selective inhibitor of elF2-alpha dephosphorylation protects
cells from ER stress. Science 307: 935-939, 2005.
4. Ernst, H.; Duncan, R. F.; Hershey, J. W. B.: Cloning and sequencing
of complementary DNAs encoding the alpha-subunit of translational
initiation factor eIF-2: characterization of the protein and its messenger
RNA. J. Biol. Chem. 262: 1206-1212, 1987.
5. Harding, H. P.; Zhang, Y.; Bertolotti, A.; Zeng, H.; Ron, D.:
Perk is essential for translational regulation and cell survival during
the unfolded protein response. Molec. Cell 5: 897-904, 2000.
6. Harding, H. P.; Zhang, Y.; Scheuner, D.; Chen, J.-J.; Kaufman,
R. J.; Ron, D.: Ppp1r15 gene knockout reveals an essential role for
translation initiation factor 2 alpha (eIF2-alpha) dephosphorylation
in mammalian development. Proc. Nat. Acad. Sci. 106: 1832-1837,
2009.
7. Hartz, P. A.: Personal Communication. Baltimore, Md. 1/28/2010.
8. Humbelin, M.; Safer, B.; Chiorini, J. A.; Hershey, J. W. B.; Cohen,
R. B.: Isolation and characterization of the promoter and flanking
regions of the gene encoding the human protein-synthesis-initiation
factor 2-alpha. Gene 81: 315-324, 1989.
9. Jacob, W. F.; Silverman, T. A.; Cohen, R. B.; Safer, B.: Identification
and characterization of a novel transcription factor participating
in the expression of eukaryotic initiation factor 2 alpha. J. Biol.
Chem. 264: 20372-20384, 1989.
10. Jousse, C.; Oyadomari, S.; Novoa, I.; Lu, P.; Zhang, Y.; Harding,
H. P.; Ron, D.: Inhibition of a constitutive translation initiation
factor 2-alpha phosphatase, CReP, promotes survival of stressed cells. J.
Cell Biol. 163: 767-775, 2003.
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*FIELD* CN
Ada Hamosh - updated: 10/19/2012
Patricia A. Hartz - updated: 2/19/2010
Patricia A. Hartz - updated: 1/28/2010
Ada Hamosh - updated: 2/10/2006
Patricia A. Hartz - updated: 11/22/2005
Marla J. F. O'Neill - updated: 7/27/2005
Patricia A. Hartz - updated: 3/3/2005
Patricia A. Hartz - updated: 9/23/2004
Stylianos E. Antonarakis - updated: 7/3/2001
*FIELD* CD
Rebekah S. Rasooly: 6/15/1999
*FIELD* ED
alopez: 10/19/2012
mgross: 2/19/2010
terry: 2/19/2010
mgross: 2/4/2010
mgross: 2/1/2010
terry: 1/28/2010
mgross: 5/21/2007
terry: 11/3/2006
alopez: 2/17/2006
terry: 2/10/2006
wwang: 11/29/2005
terry: 11/22/2005
terry: 10/4/2005
wwang: 8/3/2005
terry: 7/27/2005
mgross: 3/3/2005
mgross: 9/23/2004
mgross: 7/3/2001
alopez: 7/20/1999
alopez: 6/16/1999