ID   GCN1_HUMAN              Reviewed;        2671 AA.
AC   Q92616; A8KAY1; O95001; O95651; Q6P2S3; Q86X65; Q8N5I5; Q8WU80; Q99736;
AC   Q9UE60;
DT   01-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT   23-FEB-2022, sequence version 7.
DT   28-JAN-2026, entry version 208.
DE   RecName: Full=Stalled ribosome sensor GCN1 {ECO:0000305};
DE   AltName: Full=GCN1 eIF-2-alpha kinase activator homolog {ECO:0000312|HGNC:HGNC:4199};
DE   AltName: Full=GCN1-like protein 1 {ECO:0000250|UniProtKB:E9PVA8};
DE   AltName: Full=General control of amino-acid synthesis 1-like protein 1 {ECO:0000250|UniProtKB:E9PVA8};
DE   AltName: Full=Translational activator GCN1 {ECO:0000250|UniProtKB:E9PVA8};
DE            Short=HsGCN1;
GN   Name=GCN1 {ECO:0000303|PubMed:9234705, ECO:0000312|HGNC:HGNC:4199};
GN   Synonyms=GCN1L1 {ECO:0000250|UniProtKB:E9PVA8}, KIAA0219;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA   Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA   Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT   "Prediction of the coding sequences of unidentified human genes. VI. The
RT   coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT   cDNA clones from cell line KG-1 and brain.";
RL   DNA Res. 3:321-329(1996).
RN   [2]
RP   SEQUENCE REVISION.
RX   PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA   Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT   "Construction of expression-ready cDNA clones for KIAA genes: manual
RT   curation of 330 KIAA cDNA clones.";
RL   DNA Res. 9:99-106(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16541075; DOI=10.1038/nature04569;
RA   Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA   Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA   Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA   Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA   Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA   Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA   Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA   Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA   Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA   Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA   Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA   Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA   Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA   Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA   Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA   Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA   Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA   David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA   D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA   Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA   Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA   Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA   LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA   Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA   Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA   Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA   Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA   Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA   Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA   Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA   Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA   Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA   Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA   Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA   Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA   Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA   Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA   Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA   Gibbs R.A.;
RT   "The finished DNA sequence of human chromosome 12.";
RL   Nature 440:346-351(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Liver, and Skin;
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   PROTEIN SEQUENCE OF 2-13; 69-87; 221-229; 241-251; 314-323; 568-576;
RP   617-635; 822-829; 1201-1208; 1485-1496; 1604-1622; 1735-1745; 1960-1973;
RP   2093-2107; 2151-2161; 2192-2199; 2402-2418 AND 2522-2530, CLEAVAGE OF
RP   INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   TISSUE=B-cell lymphoma;
RA   Bienvenut W.V.;
RL   Submitted (MAR-2005) to UniProtKB.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 4-359 AND 1678-2671.
RA   Yamagata K., Oda N., Furuta H., Vaxillaire M., Southam L., Boriraj V.,
RA   Chen X., Oda Y., Takeda J., Yamada S., Nishigori H., Lebeau M.M.,
RA   Lathrop M., Cox R.D., Bell G.I.;
RT   "Transcription map of the 5cM region surrounding the hepatocyte nuclear
RT   factor-1a/MODY3 gene on chromosome 12.";
RL   Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 842-2671, AND TISSUE SPECIFICITY.
RC   TISSUE=Skeletal muscle;
RX   PubMed=9234705; DOI=10.1128/mcb.17.8.4474;
RA   Marton M.J., Vazquez de Aldana C.R., Qiu H., Chakraburtty K.,
RA   Hinnebusch A.G.;
RT   "Evidence that GCN1 and GCN20, translational regulators of GCN4, function
RT   on elongating ribosomes in activation of eIF2alpha kinase GCN2.";
RL   Mol. Cell. Biol. 17:4474-4489(1997).
RN   [8]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-786, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA   Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA   Greff Z., Keri G., Stemmann O., Mann M.;
RT   "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT   kinome across the cell cycle.";
RL   Mol. Cell 31:438-448(2008).
RN   [9]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [10]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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   [11]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-729; SER-786 AND SER-2276,
RP   AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [15]
RP   ACETYLATION AT ALA-2, AND CLEAVAGE OF INITIATOR METHIONINE.
RX   PubMed=25489052; DOI=10.1093/hmg/ddu611;
RA   Myklebust L.M., Van Damme P., Stoeve S.I., Doerfel M.J., Abboud A.,
RA   Kalvik T.V., Grauffel C., Jonckheere V., Wu Y., Swensen J., Kaasa H.,
RA   Liszczak G., Marmorstein R., Reuter N., Lyon G.J., Gevaert K., Arnesen T.;
RT   "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-
RT   acetylation defects.";
RL   Hum. Mol. Genet. 24:1956-1976(2015).
RN   [16]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [17]
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., Buerckstuemmer T.,
RA   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   [18]
RP   FUNCTION.
RX   PubMed=32610081; DOI=10.1016/j.cell.2020.06.006;
RA   Wu C.C., Peterson A., Zinshteyn B., Regot S., Green R.;
RT   "Ribosome collisions trigger general stress responses to regulate cell
RT   fate.";
RL   Cell 182:404-416(2020).
RN   [19]
RP   FUNCTION, INTERACTION WITH EIF2AK4 AND RNF14, DOMAIN, AND MUTAGENESIS OF
RP   ARG-2312.
RX   PubMed=36638793; DOI=10.1016/j.cell.2022.12.025;
RA   Oltion K., Carelli J.D., Yang T., See S.K., Wang H.Y., Kampmann M.,
RA   Taunton J.;
RT   "An E3 ligase network engages GCN1 to promote the degradation of
RT   translation factors on stalled ribosomes.";
RL   Cell 0:0-0(2023).
RN   [20]
RP   FUNCTION.
RX   PubMed=37651229; DOI=10.1016/j.celrep.2023.113056;
RA   Gurzeler L.A., Link M., Ibig Y., Schmidt I., Galuba O., Schoenbett J.,
RA   Gasser-Didierlaurant C., Parker C.N., Mao X., Bitsch F., Schirle M.,
RA   Couttet P., Sigoillot F., Ziegelmueller J., Uldry A.C., Teodorowicz W.,
RA   Schmiedeberg N., Muehlemann O., Reinhardt J.;
RT   "Drug-induced eRF1 degradation promotes readthrough and reveals a new
RT   branch of ribosome quality control.";
RL   Cell Rep. 42:113056-113056(2023).
RN   [21]
RP   FUNCTION.
RX   PubMed=37951215; DOI=10.1016/j.molcel.2023.10.011;
RA   Suryo Rahmanto A., Blum C.J., Scalera C., Heidelberger J.B., Mesitov M.,
RA   Horn-Ghetko D., Graef J.F., Mikicic I., Hobrecht R., Orekhova A.,
RA   Ostermaier M., Ebersberger S., Moeckel M.M., Krapoth N.,
RA   Da Silva Fernandes N., Mizi A., Zhu Y., Chen J.X., Choudhary C.,
RA   Papantonis A., Ulrich H.D., Schulman B.A., Koenig J., Beli P.;
RT   "K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
RT   for resolution.";
RL   Mol. Cell 0:0-0(2023).
RN   [22]
RP   FUNCTION.
RX   PubMed=37951216; DOI=10.1016/j.molcel.2023.10.012;
RA   Zhao S., Cordes J., Caban K.M., Goetz M.J., Mackens-Kiani T., Veltri A.J.,
RA   Sinha N.K., Weickert P., Kaya S., Hewitt G., Nedialkova D.D., Froehlich T.,
RA   Beckmann R., Buskirk A.R., Green R., Stingele J.;
RT   "RNF14-dependent atypical ubiquitylation promotes translation-coupled
RT   resolution of RNA-protein crosslinks.";
RL   Mol. Cell 0:0-0(2023).
CC   -!- FUNCTION: Ribosome collision sensor that plays a key role in the RNF14-
CC       RNF25 translation quality control pathway, a pathway that takes place
CC       when a ribosome has stalled during translation, and which promotes
CC       ubiquitination and degradation of translation factors on stalled
CC       ribosomes (PubMed:32610081, PubMed:36638793, PubMed:37651229,
CC       PubMed:37951215, PubMed:37951216). Directly binds to the ribosome and
CC       acts as a sentinel for colliding ribosomes: activated following
CC       ribosome stalling and promotes recruitment of RNF14, which directly
CC       ubiquitinates EEF1A1/eEF1A, leading to its degradation
CC       (PubMed:36638793, PubMed:37951215, PubMed:37951216). In addition to
CC       EEF1A1/eEF1A, the RNF14-RNF25 translation quality control pathway
CC       mediates degradation of ETF1/eRF1 and ubiquitination of ribosomal
CC       protein (PubMed:36638793, PubMed:37651229). GCN1 also acts as a
CC       positive activator of the integrated stress response (ISR) by mediating
CC       activation of EIF2AK4/GCN2 in response to amino acid starvation (By
CC       similarity). Interaction with EIF2AK4/GCN2 on translating ribosomes
CC       stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of
CC       eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) (By
CC       similarity). EIF2S1/eIF-2-alpha phosphorylation converts EIF2S1/eIF-2-
CC       alpha into a global protein synthesis inhibitor, leading to a global
CC       attenuation of cap-dependent translation, and thus to a reduced overall
CC       utilization of amino acids, while concomitantly initiating the
CC       preferential translation of ISR-specific mRNAs, such as the
CC       transcriptional activator ATF4, and hence allowing ATF4-mediated
CC       reprogramming of amino acid biosynthetic gene expression to alleviate
CC       nutrient depletion (By similarity). {ECO:0000250|UniProtKB:E9PVA8,
CC       ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:36638793,
CC       ECO:0000269|PubMed:37651229, ECO:0000269|PubMed:37951215,
CC       ECO:0000269|PubMed:37951216}.
CC   -!- SUBUNIT: Interacts with EIF2AK4/GCN2; this interaction stimulates the
CC       EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety
CC       of stress conditions, such as amino acid depletion, UV-C irradiation,
CC       proteasome inhibitor treatment and glucose deprivation
CC       (PubMed:36638793). Interacts with IMPACT; this prevents the interaction
CC       of GCN1 with EIF2AK4/GCN2 and inhibits EIF2AK4/GCN2 kinase activity (By
CC       similarity). Interacts with RNF14; interaction takes place following
CC       ribosome stalling and promotes recruitment of RNF14 (PubMed:36638793).
CC       {ECO:0000250|UniProtKB:E9PVA8, ECO:0000269|PubMed:36638793}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:E9PVA8}.
CC       Note=Associates with ribosomes in undifferentiated neuroblastoma cells
CC       and increases after neuronal differentiation.
CC       {ECO:0000250|UniProtKB:E9PVA8}.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed (PubMed:9039502). Expressed
CC       in skeletal muscules, ovary and testis (PubMed:9234705).
CC       {ECO:0000269|PubMed:9039502, ECO:0000269|PubMed:9234705}.
CC   -!- DOMAIN: The RWDBD (RWD-binding domain) region mediates binding to RWD
CC       domain-containing proteins, such as EIF2AK4/GCN2, IMPACT and RNF14.
CC       {ECO:0000269|PubMed:36638793}.
CC   -!- SIMILARITY: Belongs to the GCN1 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAC51648.1; Type=Frameshift; Evidence={ECO:0000305};
CC       Sequence=BAA13209.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; D86973; BAA13209.2; ALT_INIT; mRNA.
DR   EMBL; AC004812; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF459556; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF511175; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC004263; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC021129; AAH21129.1; -; mRNA.
DR   EMBL; BC032335; AAH32335.1; -; mRNA.
DR   EMBL; BC046177; AAH46177.1; -; mRNA.
DR   EMBL; BC064346; AAH64346.1; -; mRNA.
DR   EMBL; BC153881; AAI53882.1; -; mRNA.
DR   EMBL; U88836; AAD00655.1; -; mRNA.
DR   EMBL; U88837; AAD00656.1; -; mRNA.
DR   EMBL; U77700; AAC51648.1; ALT_FRAME; mRNA.
DR   CCDS; CCDS41847.1; -.
DR   RefSeq; NP_006827.1; NM_006836.2.
DR   AlphaFoldDB; Q92616; -.
DR   BioGRID; 116181; 415.
DR   CORUM; Q92616; -.
DR   FunCoup; Q92616; 3623.
DR   IntAct; Q92616; 187.
DR   MINT; Q92616; -.
DR   STRING; 9606.ENSP00000300648; -.
DR   ChEMBL; CHEMBL3706558; -.
DR   CarbonylDB; Q92616; -.
DR   GlyGen; Q92616; 2 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; Q92616; -.
DR   MetOSite; Q92616; -.
DR   PhosphoSitePlus; Q92616; -.
DR   SwissPalm; Q92616; -.
DR   BioMuta; GCN1; -.
DR   DMDM; 296439506; -.
DR   jPOST; Q92616; -.
DR   MassIVE; Q92616; -.
DR   PaxDb; 9606-ENSP00000300648; -.
DR   PeptideAtlas; Q92616; -.
DR   ProteomicsDB; 75364; -.
DR   Pumba; Q92616; -.
DR   Antibodypedia; 9618; 80 antibodies from 15 providers.
DR   DNASU; 10985; -.
DR   Ensembl; ENST00000300648.7; ENSP00000300648.6; ENSG00000089154.12.
DR   GeneID; 10985; -.
DR   KEGG; hsa:10985; -.
DR   MANE-Select; ENST00000300648.7; ENSP00000300648.6; NM_006836.2; NP_006827.1.
DR   UCSC; uc001txo.4; human.
DR   AGR; HGNC:4199; -.
DR   ClinPGx; PA28616; -.
DR   CTD; 10985; -.
DR   DisGeNET; 10985; -.
DR   GeneCards; GCN1; -.
DR   HGNC; HGNC:4199; GCN1.
DR   HPA; ENSG00000089154; Low tissue specificity.
DR   MIM; 605614; gene.
DR   OpenTargets; ENSG00000089154; -.
DR   VEuPathDB; HostDB:ENSG00000089154; -.
DR   eggNOG; KOG1242; Eukaryota.
DR   GeneTree; ENSGT00940000153612; -.
DR   HOGENOM; CLU_000504_2_2_1; -.
DR   InParanoid; Q92616; -.
DR   OMA; KYATQRG; -.
DR   OrthoDB; 5148094at2759; -.
DR   PAN-GO; Q92616; 4 GO annotations based on evolutionary models.
DR   PhylomeDB; Q92616; -.
DR   PathwayCommons; Q92616; -.
DR   Reactome; R-HSA-9633012; Response of EIF2AK4 (GCN2) to amino acid deficiency.
DR   SignaLink; Q92616; -.
DR   Agora; ENSG00000089154; -.
DR   BioGRID-ORCS; 10985; 359 hits in 1171 CRISPR screens.
DR   CD-CODE; 91857CE7; Nucleolus.
DR   ChiTaRS; GCN1; human.
DR   GeneWiki; GCN1L1; -.
DR   GenomeRNAi; 10985; -.
DR   Pharos; Q92616; Tbio.
DR   PRO; PR:Q92616; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; Q92616; protein.
DR   Bgee; ENSG00000089154; Expressed in ventricular zone and 213 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0022626; C:cytosolic ribosome; IDA:UniProt.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005840; C:ribosome; NAS:UniProtKB.
DR   GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR   GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB.
DR   GO; GO:0019887; F:protein kinase regulator activity; IBA:GO_Central.
DR   GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISS:UniProtKB.
DR   GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR   GO; GO:0170011; F:stalled ribosome sensor activity; IDA:UniProtKB.
DR   GO; GO:0008135; F:translation factor activity, RNA binding; NAS:UniProtKB.
DR   GO; GO:0034198; P:cellular response to amino acid starvation; IBA:GO_Central.
DR   GO; GO:0140469; P:GCN2-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0160127; P:protein-RNA covalent cross-linking repair; IDA:UniProt.
DR   GO; GO:0006417; P:regulation of translation; IBA:GO_Central.
DR   GO; GO:0072344; P:rescue of stalled ribosome; IDA:UniProtKB.
DR   FunFam; 1.25.10.10:FF:000090; eIF-2-alpha kinase activator GCN1; 1.
DR   FunFam; 1.25.10.10:FF:000096; eIF-2-alpha kinase activator gcn1; 1.
DR   FunFam; 1.25.10.10:FF:000162; GCN1, eIF2 alpha kinase activator homolog; 1.
DR   FunFam; 1.25.10.10:FF:000198; GCN1, eIF2 alpha kinase activator homolog; 1.
DR   FunFam; 1.25.10.10:FF:000226; GCN1, eIF2 alpha kinase activator homolog; 1.
DR   FunFam; 1.25.10.10:FF:000361; GCN1, eIF2 alpha kinase activator homolog; 1.
DR   Gene3D; 1.25.10.10; Leucine-rich Repeat Variant; 7.
DR   InterPro; IPR011989; ARM-like.
DR   InterPro; IPR016024; ARM-type_fold.
DR   InterPro; IPR056810; GNC1-like_N.
DR   InterPro; IPR057546; HEAT_GCN1.
DR   InterPro; IPR021133; HEAT_type_2.
DR   InterPro; IPR034085; TOG.
DR   PANTHER; PTHR23346:SF7; STALLED RIBOSOME SENSOR GCN1; 1.
DR   PANTHER; PTHR23346; TRANSLATIONAL ACTIVATOR GCN1-RELATED; 1.
DR   Pfam; PF24993; GNC1_N; 1.
DR   Pfam; PF24984; HEAT_EF3_GNC1; 1.
DR   Pfam; PF24987; HEAT_EF3_N; 2.
DR   Pfam; PF23271; HEAT_GCN1; 1.
DR   Pfam; PF25801; HEAT_GCN1_C_2; 1.
DR   SMART; SM01349; TOG; 1.
DR   SUPFAM; SSF48371; ARM repeat; 5.
DR   PROSITE; PS50077; HEAT_REPEAT; 3.
PE   1: Evidence at protein level;
KW   Acetylation; Activator; Coiled coil; Cytoplasm; Direct protein sequencing;
KW   Phosphoprotein; Proteomics identification; Reference proteome; Repeat;
KW   Stress response; Translation regulation.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:25489052, ECO:0000269|Ref.5,
FT                   ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:22223895"
FT   CHAIN           2..2671
FT                   /note="Stalled ribosome sensor GCN1"
FT                   /id="PRO_0000087443"
FT   REPEAT          140..178
FT                   /note="HEAT 1"
FT                   /evidence="ECO:0000255"
FT   REPEAT          257..293
FT                   /note="HEAT 2"
FT                   /evidence="ECO:0000255"
FT   REPEAT          294..331
FT                   /note="HEAT 3"
FT                   /evidence="ECO:0000255"
FT   REPEAT          385..423
FT                   /note="HEAT 4"
FT                   /evidence="ECO:0000255"
FT   REPEAT          425..459
FT                   /note="HEAT 5"
FT                   /evidence="ECO:0000255"
FT   REPEAT          460..503
FT                   /note="HEAT 6"
FT                   /evidence="ECO:0000255"
FT   REPEAT          560..597
FT                   /note="HEAT 7"
FT                   /evidence="ECO:0000255"
FT   REPEAT          599..636
FT                   /note="HEAT 8"
FT                   /evidence="ECO:0000255"
FT   REPEAT          697..732
FT                   /note="HEAT 9"
FT                   /evidence="ECO:0000255"
FT   REPEAT          733..770
FT                   /note="HEAT 10"
FT                   /evidence="ECO:0000255"
FT   REPEAT          879..925
FT                   /note="HEAT 11"
FT                   /evidence="ECO:0000255"
FT   REPEAT          979..1016
FT                   /note="HEAT 12"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1035..1072
FT                   /note="HEAT 13"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1078..1115
FT                   /note="HEAT 14"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1155..1192
FT                   /note="HEAT 15"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1210..1250
FT                   /note="HEAT 16"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1251..1289
FT                   /note="HEAT 17"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1290..1332
FT                   /note="HEAT 18"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1335..1372
FT                   /note="HEAT 19"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1374..1410
FT                   /note="HEAT 20"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1413..1451
FT                   /note="HEAT 21"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1455..1492
FT                   /note="HEAT 22"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1493..1530
FT                   /note="HEAT 23"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1534..1571
FT                   /note="HEAT 24"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1573..1609
FT                   /note="HEAT 25"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1611..1648
FT                   /note="HEAT 26"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1653..1690
FT                   /note="HEAT 27"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1692..1729
FT                   /note="HEAT 28"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1731..1769
FT                   /note="HEAT 29"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1773..1810
FT                   /note="HEAT 30"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1812..1848
FT                   /note="HEAT 31"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1921..1958
FT                   /note="HEAT 32"
FT                   /evidence="ECO:0000255"
FT   REPEAT          1959..1996
FT                   /note="HEAT 33"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2001..2038
FT                   /note="HEAT 34"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2039..2076
FT                   /note="HEAT 35"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2078..2106
FT                   /note="HEAT 36"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2107..2146
FT                   /note="HEAT 37"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2147..2184
FT                   /note="HEAT 38"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2188..2225
FT                   /note="HEAT 39"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2259..2296
FT                   /note="HEAT 40"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2301..2338
FT                   /note="HEAT 41"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2339..2380
FT                   /note="HEAT 42"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2382..2417
FT                   /note="HEAT 43"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2422..2459
FT                   /note="HEAT 44"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2546..2583
FT                   /note="HEAT 45"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2588..2625
FT                   /note="HEAT 46"
FT                   /evidence="ECO:0000255"
FT   REPEAT          2627..2661
FT                   /note="HEAT 47; degenerate"
FT                   /evidence="ECO:0000255"
FT   REGION          2260..2408
FT                   /note="RWDBD region"
FT                   /evidence="ECO:0000250|UniProtKB:P33892"
FT   COILED          804..863
FT                   /evidence="ECO:0000255"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000269|PubMed:25489052, ECO:0000269|Ref.5,
FT                   ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:22223895"
FT   MOD_RES         729
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         786
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18691976,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         2276
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   VARIANT         2155
FT                   /note="D -> Y (in dbSNP:rs3864938)"
FT                   /id="VAR_062228"
FT   MUTAGEN         2312
FT                   /note="R->A: Abolished interaction with RNF14 and decreased
FT                   interaction with EIF2AK4/GCN2."
FT                   /evidence="ECO:0000269|PubMed:36638793"
FT   CONFLICT        292
FT                   /note="L -> F (in Ref. 1; BAA13209 and 4; AAI53882)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        842
FT                   /note="A -> G (in Ref. 7; AAC51648)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        1584
FT                   /note="A -> V (in Ref. 7; AAC51648)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        1683
FT                   /note="A -> V (in Ref. 7; AAC51648)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        1760
FT                   /note="F -> S (in Ref. 6; AAD00655)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2298
FT                   /note="A -> V (in Ref. 7; AAC51648)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2486
FT                   /note="S -> T (in Ref. 6; AAD00655)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2549
FT                   /note="A -> R (in Ref. 7; AAC51648)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   2671 AA;  292710 MW;  FC34F505103A0158 CRC64;
     MAADTQVSET LKRFAGKVTT ASVKERREIL SELGKCVAGK DLPEGAVKGL CKLFCLTLHR
     YRDAASRRAL QAAIQQLAEA QPEATAKNLL HSLQSSGIGS KAGVPSKSSG SAALLALTWT
     CLLVRIVFPS RAKRQGDIWN KLVEVQCLLL LEVLGGSHKH AVDGAVKKLT KLWKENPGLV
     EQYLSAILSL EPNQNYAGML GLLVQFCTSH KEMDVVSQHK SALLDFYMKN ILMSKVKPPK
     YLLDSCAPLL RYLSHSEFKD LILPTIQKSL LRSPENVIET ISSLLASVTL DLSQYAMDIV
     KGLAGHLKSN SPRLMDEAVL ALRNLARQCS DSSAMESLTK HLFAILGGSE GKLTVVAQKM
     SVLSGIGSVS HHVVSGPSSQ VLNGIVAELF IPFLQQEVHE GTLVHAVSVL ALWCNRFTME
     VPKKLTEWFK KAFSLKTSTS AVRHAYLQCM LASYRGDTLL QALDLLPLLI QTVEKAASQS
     TQVPTITEGV AAALLLLKLS VADSQAEAKL SSFWQLIVDE KKQVFTSEKF LVMASEDALC
     TVLHLTERLF LDHPHRLTGN KVQQYHRALV AVLLSRTWHV RRQAQQTVRK LLSSLGGFKL
     AHGLLEELKT VLSSHKVLPL EALVTDAGEV TEAGKAYVPP RVLQEALCVI SGVPGLKGDV
     TDTEQLAQEM LIISHHPSLV AVQSGLWPAL LARMKIDPEA FITRHLDQII PRMTTQSPLN
     QSSMNAMGSL SVLSPDRVLP QLISTITASV QNPALRLVTR EEFAIMQTPA GELYDKSIIQ
     SAQQDSIKKA NMKRENKAYS FKEQIIELEL KEEIKKKKGI KEEVQLTSKQ KEMLQAQLDR
     EAQVRRRLQE LDGELEAALG LLDIILAKNP SGLTQYIPVL VDSFLPLLKS PLAAPRIKNP
     FLSLAACVMP SRLKALGTLV SHVTLRLLKP ECVLDKSWCQ EELSVAVKRA VMLLHTHTIT
     SRVGKGEPGA APLSAPAFSL VFPFLKMVLT EMPHHSEEEE EWMAQILQIL TVQAQLRASP
     NTPPGRVDEN GPELLPRVAM LRLLTWVIGT GSPRLQVLAS DTLTTLCASS SGDDGCAFAE
     QEEVDVLLCA LQSPCASVRE TVLRGLMELH MVLPAPDTDE KNGLNLLRRL WVVKFDKEEE
     IRKLAERLWS MMGLDLQPDL CSLLIDDVIY HEAAVRQAGA EALSQAVARY QRQAAEVMGR
     LMEIYQEKLY RPPPVLDALG RVISESPPDQ WEARCGLALA LNKLSQYLDS SQVKPLFQFF
     VPDALNDRHP DVRKCMLDAA LATLNTHGKE NVNSLLPVFE EFLKNAPNDA SYDAVRQSVV
     VLMGSLAKHL DKSDPKVKPI VAKLIAALST PSQQVQESVA SCLPPLVPAI KEDAGGMIQR
     LMQQLLESDK YAERKGAAYG LAGLVKGLGI LSLKQQEMMA ALTDAIQDKK NFRRREGALF
     AFEMLCTMLG KLFEPYVVHV LPHLLLCFGD GNQYVREAAD DCAKAVMSNL SAHGVKLVLP
     SLLAALEEES WRTKAGSVEL LGAMAYCAPK QLSSCLPNIV PKLTEVLTDS HVKVQKAGQQ
     ALRQIGSVIR NPEILAIAPV LLDALTDPSR KTQKCLQTLL DTKFVHFIDA PSLALIMPIV
     QRAFQDRSTD TRKMAAQIIG NMYSLTDQKD LAPYLPSVTP GLKASLLDPV PEVRTVSAKA
     LGAMVKGMGE SCFEDLLPWL METLTYEQSS VDRSGAAQGL AEVMAGLGVE KLEKLMPEIV
     ATASKVDIAP HVRDGYIMMF NYLPITFGDK FTPYVGPIIP CILKALADEN EFVRDTALRA
     GQRVISMYAE TAIALLLPQL EQGLFDDLWR IRFSSVQLLG DLLFHISGVT GKMTTETASE
     DDNFGTAQSN KAIITALGVE RRNRVLAGLY MGRSDTQLVV RQASLHVWKI VVSNTPRTLR
     EILPTLFGLL LGFLASTCAD KRTIAARTLG DLVRKLGEKI LPEIIPILEE GLRSQKSDER
     QGVCIGLSEI MKSTSRDAVL YFSESLVPTA RKALCDPLEE VREAAAKTFE QLHSTIGHQA
     LEDILPFLLK QLDDEEVSEF ALDGLKQVMA IKSRVVLPYL VPKLTTPPVN TRVLAFLSSV
     AGDALTRHLG VILPAVMLAL KEKLGTPDEQ LEMANCQAVI LSVEDDTGHR IIIEDLLEAT
     RSPEVGMRQA AAIILNIYCS RSKADYTSHL RSLVSGLIRL FNDSSPVVLE ESWDALNAIT
     KKLDAGNQLA LIEELHKEIR LIGNESKGEH VPGFCLPKKG VTSILPVLRE GVLTGSPEQK
     EEAAKALGLV IRLTSADALR PSVVSITGPL IRILGDRFSW NVKAALLETL SLLLAKVGIA
     LKPFLPQLQT TFTKALQDSN RGVRLKAADA LGKLISIHIK VDPLFTELLN GIRAMEDPGV
     RDTMLQALRF VIQGAGAKVD AVIRKNIVSL LLSMLGHDED NTRISSAGCL GELCAFLTEE
     ELSAVLQQCL LADVSGIDWM VRHGRSLALS VAVNVAPGRL CAGRYSSDVQ EMILSSATAD
     RIPIAVSGVR GMGFLMRHHI ETGGGQLPAK LSSLFVKCLQ NPSSDIRLVA EKMIWWANKD
     PLPPLDPQAI KPILKALLDN TKDKNTVVRA YSDQAIVNLL KMRQGEEVFQ SLSKILDVAS
     LEVLNEVNRR SLKKLASQAD STEQVDDTIL T
//