RAG1_HUMAN
ID RAG1_HUMAN Reviewed; 1043 AA.
AC P15918; E9PPC4; Q8IY72; Q8NER2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 2.
DT 03-AUG-2022, entry version 224.
DE RecName: Full=V(D)J recombination-activating protein 1;
DE Short=RAG-1;
DE AltName: Full=RING finger protein 74;
DE Includes:
DE RecName: Full=Endonuclease RAG1;
DE EC=3.1.-.-;
DE Includes:
DE RecName: Full=E3 ubiquitin-protein ligase RAG1;
DE EC=2.3.2.27;
DE AltName: Full=RING-type E3 ubiquitin transferase RAG1 {ECO:0000305};
GN Name=RAG1; Synonyms=RNF74;
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 [MRNA] (ISOFORM 1), AND VARIANT ARG-249.
RX PubMed=2598259; DOI=10.1016/0092-8674(89)90760-5;
RA Schatz D.G., Oettinger M.A., Baltimore D.;
RT "The V(D)J recombination activating gene, RAG-1.";
RL Cell 59:1035-1048(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ARG-249.
RC TISSUE=Testis;
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 IDENTIFICATION OF IMPORTIN ALPHA-1 BINDING DOMAIN.
RX PubMed=8052633; DOI=10.1073/pnas.91.16.7633;
RA Cortes P., Ye Z.-S., Baltimore D.;
RT "RAG-1 interacts with the repeated amino acid motif of the human homologue
RT of the yeast protein SRP1.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7633-7637(1994).
RN [6]
RP VARIANTS GLY-244 AND ARG-249.
RX PubMed=8844221;
RX DOI=10.1002/(sici)1098-1004(1996)8:2<191::aid-humu15>3.0.co;2-y;
RA Nomdedeu J.F., Lasa A., Seminago R., Rubiol E., Baiget M., Soler J.;
RT "Two new variants of RAG-1 protein predicted by SSCP.";
RL Hum. Mutat. 8:191-192(1996).
RN [7]
RP VARIANTS T(-)B(-)NK(+) SCID HIS-624; LYS-722; 774-GLU--PHE-1043 DEL;
RP 897-ARG--PHE-1043 DEL AND 938-TYR--PHE-1043 DEL, VARIANT VAL-156,
RP CHARACTERIZATION OF VARIANT VAL-156, AND CHARACTERIZATION OF VARIANTS
RP T(-)B(-)NK(+) SCID HIS-624; LYS-722 AND 938-TYR--PHE-1043 DEL.
RX PubMed=8810255; DOI=10.1126/science.274.5284.97;
RA Schwarz K., Gauss G.H., Ludwig L., Pannicke U., Li Z., Linder D.,
RA Friedrich W., Seger R.A., Hansen-Hagge T.E., Desiderio S., Lieber M.R.,
RA Bartram C.R.;
RT "RAG mutations in human B cell-negative SCID.";
RL Science 274:97-99(1996).
RN [8]
RP VARIANTS OS CYS-396; HIS-396; GLY-429; HIS-561; CYS-561; HIS-737 AND
RP CYS-912.
RX PubMed=9630231; DOI=10.1016/s0092-8674(00)81448-8;
RA Villa A., Santagata S., Bozzi F., Giliani S., Frattini A., Imberti L.,
RA Gatta L.B., Ochs H.D., Schwarz K., Notarangelo L.D., Vezzoni P.,
RA Spanopoulou E.;
RT "Partial V(D)J recombination activity leads to Omenn syndrome.";
RL Cell 93:885-896(1998).
RN [9]
RP VARIANTS OS CYS-396 AND ARG-885.
RX PubMed=10606976; DOI=10.1046/j.1365-2249.2000.01101.x;
RA Wada T., Takei K., Kudo M., Shimura S., Kasahara Y., Koizumi S.,
RA Kawa-Ha K., Ishida Y., Imashuku S., Seki H., Yachie A.;
RT "Characterization of immune function and analysis of RAG gene mutations in
RT Omenn syndrome and related disorders.";
RL Clin. Exp. Immunol. 119:148-155(2000).
RN [10]
RP VARIANTS OS TYR-328; LEU-396; PRO-401; GLN-410; MET-433; VAL-435; VAL-444;
RP HIS-474; TRP-507; CYS-522 SER-559; CYS-624; GLY-669; LEU-753 AND GLN-975,
RP AND VARIANT ILE-855.
RX PubMed=11133745; DOI=10.1182/blood.v97.1.81;
RA Villa A., Sobacchi C., Notarangelo L.D., Bozzi F., Abinun M.,
RA Abrahamsen T.G., Arkwright P.D., Baniyash M., Brooks E.G., Conley M.E.,
RA Cortes P., Duse M., Fasth A., Filipovich A.M., Infante A.J., Jones A.,
RA Mazzolari E., Muller S.M., Pasic S., Rechavi G., Sacco M.G., Santagata S.,
RA Schroeder M.L., Seger R., Strina D., Ugazio A., Vaeliaho J., Vihinen M.,
RA Vogler L.B., Ochs H., Vezzoni P., Friedrich W., Schwarz K.;
RT "V(D)J recombination defects in lymphocytes due to RAG mutations: severe
RT immunodeficiency with a spectrum of clinical presentations.";
RL Blood 97:81-88(2001).
RN [11]
RP VARIANTS SER-559 AND 897-ARG--PHE-1043 DEL, AND CHARACTERIZATION OF
RP VARIANTS SER-559 AND 897-ARG--PHE-1043 DEL.
RX PubMed=11520796; DOI=10.1182/blood.v98.5.1464;
RA Kumaki S., Villa A., Asada H., Kawai S., Ohashi Y., Takahashi M.,
RA Hakozaki I., Nitanai E., Minegishi M., Tsuchiya S.;
RT "Identification of anti-herpes simplex virus antibody-producing B cells in
RT a patient with an atypical RAG1 immunodeficiency.";
RL Blood 98:1464-1468(2001).
RN [12]
RP VARIANTS T-CMVA TRP-841 AND PRO-981.
RX PubMed=16276422; DOI=10.1172/jci25178;
RA de Villartay J.-P., Lim A., Al-Mousa H., Dupont S., Dechanet-Merville J.,
RA Coumau-Gatbois E., Gougeon M.-L., Lemainque A., Eidenschenk C.,
RA Jouanguy E., Abel L., Casanova J.-L., Fischer A., Le Deist F.;
RT "A novel immunodeficiency associated with hypomorphic RAG1 mutations and
RT CMV infection.";
RL J. Clin. Invest. 115:3291-3299(2005).
RN [13]
RP VARIANTS CHIDG TRP-314; TRP-507; HIS-737; GLN-778 AND TRP-975, AND
RP CHARACTERIZATION OF VARIANTS CHIDG TRP-314; TRP-507; HIS-737; GLN-778 AND
RP TRP-975.
RX PubMed=18463379; DOI=10.1056/nejmoa073966;
RA Schuetz C., Huck K., Gudowius S., Megahed M., Feyen O., Hubner B.,
RA Schneider D.T., Manfras B., Pannicke U., Willemze R., Knuechel R.,
RA Goebel U., Schulz A., Borkhardt A., Friedrich W., Schwarz K., Niehues T.;
RT "An immunodeficiency disease with RAG mutations and granulomas.";
RL N. Engl. J. Med. 358:2030-2038(2008).
RN [14]
RP VARIANTS T(-)B(-)NK(+) SCID MET-433; SER-559 AND HIS-624, AND VARIANTS OS
RP HIS-396 AND PRO-401.
RX PubMed=19912631; DOI=10.1186/1471-2350-10-116;
RA Alsmadi O., Al-Ghonaium A., Al-Muhsen S., Arnaout R., Al-Dhekri H.,
RA Al-Saud B., Al-Kayal F., Al-Saud H., Al-Mousa H.;
RT "Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn
RT syndrome cases in Saudi Arabia.";
RL BMC Med. Genet. 10:116-116(2009).
RN [15]
RP VARIANT CYS-474.
RX PubMed=20956421; DOI=10.1542/peds.2009-3171;
RA Avila E.M., Uzel G., Hsu A., Milner J.D., Turner M.L., Pittaluga S.,
RA Freeman A.F., Holland S.M.;
RT "Highly variable clinical phenotypes of hypomorphic RAG1 mutations.";
RL Pediatrics 126:E1248-E1252(2010).
RN [16]
RP VARIANT OS GLN-454.
RX PubMed=21624848; DOI=10.1016/j.clim.2011.04.011;
RA Dalal I., Tasher D., Somech R., Etzioni A., Garti B.Z., Lev D., Cohen S.,
RA Somekh E., Leshinsky-Silver E.;
RT "Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting
RT with T-B-SCID or Omenn syndrome.";
RL Clin. Immunol. 140:284-290(2011).
RN [17]
RP VARIANT OS TRP-699.
RX PubMed=21771083; DOI=10.1111/j.1399-3038.2010.01126.x;
RA Zhang Z.Y., Zhao X.D., Jiang L.P., Liu E.M., Cui Y.X., Wang M., Wei H.,
RA Yu J., An Y.F., Yang X.Q.;
RT "Clinical characteristics and molecular analysis of three Chinese children
RT with Omenn syndrome.";
RL Pediatr. Allergy Immunol. 22:482-487(2011).
RN [18]
RP VARIANT TYR-358, AND CHARACTERIZATION OF VARIANT TYR-358.
RX PubMed=24996264; DOI=10.1016/j.jaci.2014.04.042;
RA Abolhassani H., Wang N., Aghamohammadi A., Rezaei N., Lee Y.N., Frugoni F.,
RA Notarangelo L.D., Pan-Hammarstroem Q., Hammarstroem L.;
RT "A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in
RT a phenotype resembling common variable immunodeficiency.";
RL J. Allergy Clin. Immunol. 134:1375-1380(2014).
RN [19]
RP VARIANTS CYS-522; ARG-612 AND 897-ARG--PHE-1043 DEL.
RX PubMed=25516070; DOI=10.1007/s10875-014-0121-5;
RA Buchbinder D., Baker R., Lee Y.N., Ravell J., Zhang Y., McElwee J.,
RA Nugent D., Coonrod E.M., Durtschi J.D., Augustine N.H., Voelkerding K.V.,
RA Csomos K., Rosen L., Browne S., Walter J.E., Notarangelo L.D., Hill H.R.,
RA Kumanovics A.;
RT "Identification of patients with RAG mutations previously diagnosed with
RT common variable immunodeficiency disorders.";
RL J. Clin. Immunol. 35:119-124(2015).
RN [20]
RP VARIANTS ASP-375 AND CYS-474, AND CHARACTERIZATION OF VARIANT CYS-474.
RX PubMed=28216420; DOI=10.1016/j.clim.2016.12.013;
RA Schroeder C., Baerlecken N.T., Pannicke U., Doerk T., Witte T., Jacobs R.,
RA Stoll M., Schwarz K., Grimbacher B., Schmidt R.E., Atschekzei F.;
RT "Evaluation of RAG1 mutations in an adult with combined immunodeficiency
RT and progressive multifocal leukoencephalopathy.";
RL Clin. Immunol. 179:1-7(2017).
CC -!- FUNCTION: Catalytic component of the RAG complex, a multiprotein
CC complex that mediates the DNA cleavage phase during V(D)J
CC recombination. V(D)J recombination assembles a diverse repertoire of
CC immunoglobulin and T-cell receptor genes in developing B and T-
CC lymphocytes through rearrangement of different V (variable), in some
CC cases D (diversity), and J (joining) gene segments. In the RAG complex,
CC RAG1 mediates the DNA-binding to the conserved recombination signal
CC sequences (RSS) and catalyzes the DNA cleavage activities by
CC introducing a double-strand break between the RSS and the adjacent
CC coding segment. RAG2 is not a catalytic component but is required for
CC all known catalytic activities. DNA cleavage occurs in 2 steps: a first
CC nick is introduced in the top strand immediately upstream of the
CC heptamer, generating a 3'-hydroxyl group that can attack the
CC phosphodiester bond on the opposite strand in a direct
CC transesterification reaction, thereby creating 4 DNA ends: 2 hairpin
CC coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin
CC structure plays an essential role in the V(D)J recombination reactions
CC and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3)
CC stimulates both the nicking and haipinning steps. The RAG complex also
CC plays a role in pre-B cell allelic exclusion, a process leading to
CC expression of a single immunoglobulin heavy chain allele to enforce
CC clonality and monospecific recognition by the B-cell antigen receptor
CC (BCR) expressed on individual B-lymphocytes. The introduction of DNA
CC breaks by the RAG complex on one immunoglobulin allele induces ATM-
CC dependent repositioning of the other allele to pericentromeric
CC heterochromatin, preventing accessibility to the RAG complex and
CC recombination of the second allele. In addition to its endonuclease
CC activity, RAG1 also acts as an E3 ubiquitin-protein ligase that
CC mediates monoubiquitination of histone H3. Histone H3
CC monoubiquitination is required for the joining step of V(D)J
CC recombination. Mediates polyubiquitination of KPNA1 (By similarity).
CC {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250};
CC Note=Binds 1 divalent metal cation per subunit. Mg(2+) or Mn(2+).
CC {ECO:0000250};
CC -!- SUBUNIT: Homodimer. Component of the RAG complex composed of core
CC components RAG1 and RAG2, and associated component HMGB1 or HMGB2.
CC Interacts with DCAF1, leading to recruitment of the CUL4A-RBX1-DDB1-
CC DCAF1/VPRBP complex to ubiquitinate proteins and limit error-prone
CC repair during V(D)J recombination (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P15918; P16333: NCK1; NbExp=2; IntAct=EBI-1755109, EBI-389883;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00820}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P15918-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P15918-2; Sequence=VSP_055883;
CC -!- TISSUE SPECIFICITY: Maturing lymphoid cells.
CC -!- DOMAIN: The RING-type zinc finger mediates the E3 ubiquitin-protein
CC ligase activity. {ECO:0000250}.
CC -!- DOMAIN: The NBD (nonamer binding) DNA-binding domain mediates the
CC specific binding to the nonamer RSS motif by forming a tightly
CC interwoven homodimer that binds and synapses 2 nonamer elements, with
CC each NBD making contact with both DNA molecules. Each RSS is composed
CC of well-conserved heptamer (consensus 5'-CACAGTG-3') and nonamer
CC (consensus 5'-ACAAAAACC-3') sequences separated by a spacer of either
CC 12 bp or 23 bp. {ECO:0000255|PROSITE-ProRule:PRU00820}.
CC -!- PTM: Autoubiquitinated in the presence of CDC34/UBCH3. {ECO:0000250}.
CC -!- DISEASE: Combined cellular and humoral immune defects with granulomas
CC (CHIDG) [MIM:233650]: Immunodeficiency disease with granulomas in the
CC skin, mucous membranes, and internal organs. Other characteristics
CC include hypogammaglobulinemia, a diminished number of T and B-cells,
CC and sparse thymic tissue on ultrasonography.
CC {ECO:0000269|PubMed:18463379}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Severe combined immunodeficiency autosomal recessive T-cell-
CC negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID)
CC [MIM:601457]: A form of severe combined immunodeficiency (SCID), a
CC genetically and clinically heterogeneous group of rare congenital
CC disorders characterized by impairment of both humoral and cell-mediated
CC immunity, leukopenia, and low or absent antibody levels. Patients
CC present in infancy recurrent, persistent infections by opportunistic
CC organisms. The common characteristic of all types of SCID is absence of
CC T-cell-mediated cellular immunity due to a defect in T-cell
CC development. {ECO:0000269|PubMed:19912631, ECO:0000269|PubMed:8810255}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Omenn syndrome (OS) [MIM:603554]: Severe immunodeficiency
CC characterized by the presence of activated, anergic, oligoclonal T-
CC cells, hypereosinophilia, and high IgE levels.
CC {ECO:0000269|PubMed:10606976, ECO:0000269|PubMed:11133745,
CC ECO:0000269|PubMed:19912631, ECO:0000269|PubMed:21624848,
CC ECO:0000269|PubMed:21771083, ECO:0000269|PubMed:9630231}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Alpha/beta T-cell lymphopenia, with gamma/delta T-cell
CC expansion, severe cytomegalovirus infection and autoimmunity (T-CMVA)
CC [MIM:609889]: An immunological disorder characterized by oligoclonal
CC expansion of TCR gamma/delta T-cells, TCR alpha/beta T-cell
CC lymphopenia, severe, disseminated cytomegalovirus infection and
CC autoimmune cytopenia. {ECO:0000269|PubMed:16276422}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RAG1 family. {ECO:0000255|PROSITE-
CC ProRule:PRU00820}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAM77798.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/rag1/";
CC -!- WEB RESOURCE: Name=RAG1base; Note=RAG1 deficiency database;
CC URL="http://structure.bmc.lu.se/idbase/RAG1base/";
CC -!- WEB RESOURCE: Name=Mendelian genes recombination activating gene 1
CC (RAG1); Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/RAG1";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M29474; AAA60248.1; -; mRNA.
DR EMBL; AY130302; AAM77798.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC061999; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC139427; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC037344; AAH37344.1; -; mRNA.
DR CCDS; CCDS7902.1; -. [P15918-1]
DR PIR; A33754; A33754.
DR RefSeq; NP_000439.1; NM_000448.2. [P15918-1]
DR RefSeq; XP_005253098.1; XM_005253041.4.
DR RefSeq; XP_011518552.1; XM_011520250.2.
DR AlphaFoldDB; P15918; -.
DR SMR; P15918; -.
DR BioGRID; 111832; 30.
DR CORUM; P15918; -.
DR IntAct; P15918; 15.
DR MINT; P15918; -.
DR STRING; 9606.ENSP00000299440; -.
DR CarbonylDB; P15918; -.
DR iPTMnet; P15918; -.
DR PhosphoSitePlus; P15918; -.
DR BioMuta; RAG1; -.
DR DMDM; 313104166; -.
DR MassIVE; P15918; -.
DR PaxDb; P15918; -.
DR PeptideAtlas; P15918; -.
DR PRIDE; P15918; -.
DR Antibodypedia; 42779; 122 antibodies from 26 providers.
DR DNASU; 5896; -.
DR Ensembl; ENST00000299440.6; ENSP00000299440.5; ENSG00000166349.10. [P15918-1]
DR Ensembl; ENST00000534663.1; ENSP00000434610.1; ENSG00000166349.10. [P15918-2]
DR GeneID; 5896; -.
DR KEGG; hsa:5896; -.
DR MANE-Select; ENST00000299440.6; ENSP00000299440.5; NM_000448.3; NP_000439.2.
DR UCSC; uc001mwt.4; human. [P15918-1]
DR CTD; 5896; -.
DR DisGeNET; 5896; -.
DR GeneCards; RAG1; -.
DR HGNC; HGNC:9831; RAG1.
DR HPA; ENSG00000166349; Tissue enriched (lymphoid).
DR MalaCards; RAG1; -.
DR MIM; 179615; gene.
DR MIM; 233650; phenotype.
DR MIM; 601457; phenotype.
DR MIM; 603554; phenotype.
DR MIM; 609889; phenotype.
DR neXtProt; NX_P15918; -.
DR OpenTargets; ENSG00000166349; -.
DR Orphanet; 231154; Combined immunodeficiency due to partial RAG1 deficiency.
DR Orphanet; 157949; Combined immunodeficiency with granulomatosis.
DR Orphanet; 39041; Omenn syndrome.
DR Orphanet; 331206; Severe combined immunodeficiency due to complete RAG1/2 deficiency.
DR PharmGKB; PA34185; -.
DR VEuPathDB; HostDB:ENSG00000166349; -.
DR eggNOG; ENOG502QSFV; Eukaryota.
DR GeneTree; ENSGT00390000008679; -.
DR HOGENOM; CLU_010909_0_0_1; -.
DR InParanoid; P15918; -.
DR OMA; WKFKLFK; -.
DR OrthoDB; 85196at2759; -.
DR PhylomeDB; P15918; -.
DR TreeFam; TF331926; -.
DR PathwayCommons; P15918; -.
DR Reactome; R-HSA-1266695; Interleukin-7 signaling.
DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR SignaLink; P15918; -.
DR SIGNOR; P15918; -.
DR BioGRID-ORCS; 5896; 10 hits in 1121 CRISPR screens.
DR GenomeRNAi; 5896; -.
DR Pharos; P15918; Tbio.
DR PRO; PR:P15918; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P15918; protein.
DR Bgee; ENSG00000166349; Expressed in thymus and 102 other tissues.
DR Genevisible; P15918; HS.
DR GO; GO:0097519; C:DNA recombinase complex; IBA:GO_Central.
DR GO; GO:1905347; C:endodeoxyribonuclease complex; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; TAS:ProtInc.
DR GO; GO:0004519; F:endonuclease activity; ISS:UniProtKB.
DR GO; GO:0042393; F:histone binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IBA:GO_Central.
DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0006310; P:DNA recombination; TAS:ProtInc.
DR GO; GO:0010390; P:histone monoubiquitination; ISS:UniProtKB.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0070244; P:negative regulation of thymocyte apoptotic process; IEA:Ensembl.
DR GO; GO:0045582; P:positive regulation of T cell differentiation; IEA:Ensembl.
DR GO; GO:0002331; P:pre-B cell allelic exclusion; ISS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; ISS:UniProtKB.
DR GO; GO:2000822; P:regulation of behavioral fear response; IEA:Ensembl.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB.
DR GO; GO:0043029; P:T cell homeostasis; IEA:Ensembl.
DR GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR GO; GO:0033151; P:V(D)J recombination; IMP:CACAO.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR024627; RAG1.
DR InterPro; IPR035714; RAG1_imp-bd.
DR InterPro; IPR019485; RAG1_Znf.
DR InterPro; IPR023336; RAG_nonamer-bd_dom.
DR InterPro; IPR036236; Znf_C2H2_sf.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR11539; PTHR11539; 1.
DR Pfam; PF12940; RAG1; 1.
DR Pfam; PF12560; RAG1_imp_bd; 1.
DR Pfam; PF10426; zf-RAG1; 1.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF57667; SSF57667; 1.
DR PROSITE; PS51487; NBD; 1.
DR PROSITE; PS51765; ZF_RAG1; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chromatin regulator; Disease variant;
KW DNA recombination; DNA-binding; Endonuclease; Hydrolase; Isopeptide bond;
KW Metal-binding; Multifunctional enzyme; Nuclease; Nucleus;
KW Reference proteome; SCID; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..1043
FT /note="V(D)J recombination-activating protein 1"
FT /id="PRO_0000056004"
FT ZN_FING 293..332
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 354..383
FT /note="RAG1-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01101"
FT DNA_BIND 392..459
FT /note="NBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00820"
FT REGION 1..288
FT /note="Interaction with importin alpha-1"
FT REGION 40..80
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 40..56
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 269
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 273
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 293
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 296
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 296
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 298
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 308
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 310
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 313
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 316
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 328
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 331
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 358
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01101"
FT BINDING 363
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01101"
FT BINDING 375
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01101"
FT BINDING 379
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01101"
FT BINDING 603
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 711
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT BINDING 965
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250"
FT SITE 896
FT /note="Essential for DNA hairpin formation, participates in
FT base-stacking interactions near the cleavage site"
FT /evidence="ECO:0000250"
FT CROSSLNK 234
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P15919"
FT VAR_SEQ 931..1043
FT /note="YEGKITNYFHKTLAHVPEIIERDGSIGAWASEGNESGNKLFRRFRKMNARQS
FT KCYEMEDVLKHHWLYTSKYLQKFMNAHNALKTSGFTMNPQASLGDPLGIEDSLESQDSM
FT EF -> N (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_055883"
FT VARIANT 156
FT /note="A -> V (no effect on recombination activity;
FT dbSNP:rs1801203)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_007800"
FT VARIANT 169
FT /note="S -> L (in dbSNP:rs4151027)"
FT /id="VAR_029260"
FT VARIANT 244
FT /note="R -> G (in dbSNP:rs199474683)"
FT /evidence="ECO:0000269|PubMed:8844221"
FT /id="VAR_007801"
FT VARIANT 247
FT /note="R -> H (in dbSNP:rs4151029)"
FT /id="VAR_029261"
FT VARIANT 249
FT /note="H -> R (in dbSNP:rs3740955)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:2598259, ECO:0000269|PubMed:8844221"
FT /id="VAR_007802"
FT VARIANT 302
FT /note="D -> E (in dbSNP:rs4151030)"
FT /id="VAR_020113"
FT VARIANT 314
FT /note="R -> W (in CHIDG; reduced recombination activity;
FT dbSNP:rs121918568)"
FT /evidence="ECO:0000269|PubMed:18463379"
FT /id="VAR_045957"
FT VARIANT 328
FT /note="C -> Y (in OS; dbSNP:rs121918571)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025971"
FT VARIANT 358
FT /note="C -> Y (found in a patient with common variable
FT immunodeficiency with B cell deficiency; decreased
FT recombinant activity)"
FT /evidence="ECO:0000269|PubMed:24996264"
FT /id="VAR_078305"
FT VARIANT 375
FT /note="H -> D (found in a patient with T and B cell
FT immunodeficiency and progressive multifocal
FT leukoencephalopathy; unknown pathological significance;
FT dbSNP:rs773272902)"
FT /evidence="ECO:0000269|PubMed:28216420"
FT /id="VAR_078306"
FT VARIANT 396
FT /note="R -> C (in OS; dbSNP:rs104894289)"
FT /evidence="ECO:0000269|PubMed:10606976,
FT ECO:0000269|PubMed:9630231"
FT /id="VAR_008886"
FT VARIANT 396
FT /note="R -> H (in OS; dbSNP:rs104894291)"
FT /evidence="ECO:0000269|PubMed:19912631,
FT ECO:0000269|PubMed:9630231"
FT /id="VAR_008887"
FT VARIANT 396
FT /note="R -> L (in OS; dbSNP:rs104894291)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025972"
FT VARIANT 401
FT /note="S -> P (in OS; dbSNP:rs199474682)"
FT /evidence="ECO:0000269|PubMed:11133745,
FT ECO:0000269|PubMed:19912631"
FT /id="VAR_025973"
FT VARIANT 410
FT /note="R -> Q (in OS; found in patients with an atypical
FT form of severe combined immunodeficiency/Omenn syndrome;
FT dbSNP:rs199474684)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025974"
FT VARIANT 429
FT /note="D -> G (in OS; dbSNP:rs104894292)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008888"
FT VARIANT 433
FT /note="V -> M (in OS and T(-)B(-)NK(+) SCID; found in a
FT patient with an atypical form of severe combined
FT immunodeficiency/Omenn syndrome; dbSNP:rs199474679)"
FT /evidence="ECO:0000269|PubMed:11133745,
FT ECO:0000269|PubMed:19912631"
FT /id="VAR_025975"
FT VARIANT 435
FT /note="M -> V (in OS; dbSNP:rs141524540)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025976"
FT VARIANT 444
FT /note="A -> V (in OS; found in patients with an atypical
FT form of severe combined immunodeficiency/Omenn syndrome;
FT dbSNP:rs199474685)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025977"
FT VARIANT 449
FT /note="R -> K (in dbSNP:rs4151031)"
FT /id="VAR_029262"
FT VARIANT 454
FT /note="L -> Q (in OS; dbSNP:rs199474677)"
FT /evidence="ECO:0000269|PubMed:21624848"
FT /id="VAR_067274"
FT VARIANT 474
FT /note="R -> C (probable disease-associated variant found in
FT a patient with relatively late onset of infections and
FT isolated T-cell lymphopenia; also found in a patient with T
FT and B cell immunodeficiency and progressive multifocal
FT leukoencephalopathy; decreases recombination activity; no
FT effect on protein abundance; dbSNP:rs199474678)"
FT /evidence="ECO:0000269|PubMed:20956421,
FT ECO:0000269|PubMed:28216420"
FT /id="VAR_067275"
FT VARIANT 474
FT /note="R -> H (in OS; found in patients with an atypical
FT form of severe combined immunodeficiency/Omenn syndrome;
FT dbSNP:rs199474686)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025978"
FT VARIANT 507
FT /note="R -> W (in CHIDG and OS; found in patients with an
FT atypical form of severe combined immunodeficiency/Omenn
FT syndrome; reduced recombination activity when associated
FT with H-737; dbSNP:rs104894298)"
FT /evidence="ECO:0000269|PubMed:11133745,
FT ECO:0000269|PubMed:18463379"
FT /id="VAR_025979"
FT VARIANT 522
FT /note="W -> C (in OS; also found in patients with an
FT atypical form of severe combined immunodeficiency/Omenn
FT syndrome; dbSNP:rs193922461)"
FT /evidence="ECO:0000269|PubMed:11133745,
FT ECO:0000269|PubMed:25516070"
FT /id="VAR_025980"
FT VARIANT 525
FT /note="P -> S (in dbSNP:rs4151032)"
FT /id="VAR_029263"
FT VARIANT 559
FT /note="R -> S (in T(-)B(-)NK(+) SCID and OS; also found in
FT a patient with an atypical form of severe combined
FT immunodeficiency/Omenn syndrome; decreased recombination
FT activity; dbSNP:rs199474681)"
FT /evidence="ECO:0000269|PubMed:11133745,
FT ECO:0000269|PubMed:11520796, ECO:0000269|PubMed:19912631"
FT /id="VAR_025981"
FT VARIANT 561
FT /note="R -> C (in OS; dbSNP:rs104894285)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008890"
FT VARIANT 561
FT /note="R -> H (in OS; dbSNP:rs104894284)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008889"
FT VARIANT 612
FT /note="H -> R (found in a patient with an atypical form of
FT combined immunodeficiency; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25516070"
FT /id="VAR_078307"
FT VARIANT 624
FT /note="R -> C (in OS; dbSNP:rs199474688)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025982"
FT VARIANT 624
FT /note="R -> H (in T(-)B(-)NK(+) SCID; decreased
FT recombination activity; dbSNP:rs199474680)"
FT /evidence="ECO:0000269|PubMed:19912631,
FT ECO:0000269|PubMed:8810255"
FT /id="VAR_007803"
FT VARIANT 669
FT /note="E -> G (in OS; dbSNP:rs199474689)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025983"
FT VARIANT 699
FT /note="R -> W (in OS; also in a patient with multiple
FT autoimmune disorders; dbSNP:rs199474676)"
FT /evidence="ECO:0000269|PubMed:21771083"
FT /id="VAR_067276"
FT VARIANT 722
FT /note="E -> K (in T(-)B(-)NK(+) SCID; decreased
FT recombination activity; dbSNP:rs28933392)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_007804"
FT VARIANT 737
FT /note="R -> H (in OS and CHIDG; reduced recombination
FT activity when associated with T-507; dbSNP:rs104894286)"
FT /evidence="ECO:0000269|PubMed:18463379,
FT ECO:0000269|PubMed:9630231"
FT /id="VAR_008891"
FT VARIANT 753
FT /note="H -> L (in OS; found in patients with an atypical
FT form of severe combined immunodeficiency/Omenn syndrome;
FT dbSNP:rs199474687)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025984"
FT VARIANT 774..1043
FT /note="Missing (in T(-)B(-)NK(+) SCID; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_078308"
FT VARIANT 778
FT /note="R -> Q (in CHIDG; reduced recombination activity;
FT dbSNP:rs121918569)"
FT /evidence="ECO:0000269|PubMed:18463379"
FT /id="VAR_045958"
FT VARIANT 820
FT /note="K -> R (in dbSNP:rs2227973)"
FT /id="VAR_008892"
FT VARIANT 841
FT /note="R -> W (in T-CMVA; also found in a patient with an
FT atypical form of severe combined immunodeficiency /Omenn
FT syndrome; dbSNP:rs104894287)"
FT /evidence="ECO:0000269|PubMed:16276422"
FT /id="VAR_025985"
FT VARIANT 855
FT /note="N -> I (probable disease-associated variant found in
FT a patient with severe combined immunodeficiency with
FT maternal fetal engraftment; dbSNP:rs199474690)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025986"
FT VARIANT 880
FT /note="E -> K (in dbSNP:rs4151033)"
FT /id="VAR_020114"
FT VARIANT 885
FT /note="L -> R (in OS; dbSNP:rs199474691)"
FT /evidence="ECO:0000269|PubMed:10606976"
FT /id="VAR_008893"
FT VARIANT 887
FT /note="D -> N (in dbSNP:rs4151034)"
FT /id="VAR_029264"
FT VARIANT 897..1043
FT /note="Missing (in T(-)B(-)NK(+) SCID; also found in
FT patients with an atypical form of severe combined
FT immunodeficiency/Omenn syndrome; loss of recombination
FT activity; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:11520796,
FT ECO:0000269|PubMed:25516070, ECO:0000269|PubMed:8810255"
FT /id="VAR_078309"
FT VARIANT 912
FT /note="Y -> C (in OS; dbSNP:rs104894290)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008894"
FT VARIANT 938..1043
FT /note="Missing (in T(-)B(-)NK(+) SCID; decreased
FT recombination activity)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_078310"
FT VARIANT 975
FT /note="R -> Q (in OS; dbSNP:rs150739647)"
FT /evidence="ECO:0000269|PubMed:11133745"
FT /id="VAR_025987"
FT VARIANT 975
FT /note="R -> W (in CHIDG; reduced recombination activity;
FT dbSNP:rs121918570)"
FT /evidence="ECO:0000269|PubMed:18463379"
FT /id="VAR_045959"
FT VARIANT 981
FT /note="Q -> P (in T-CMVA; dbSNP:rs104894288)"
FT /evidence="ECO:0000269|PubMed:16276422"
FT /id="VAR_025988"
SQ SEQUENCE 1043 AA; 119097 MW; 5417A7413DA8CB65 CRC64;
MAASFPPTLG LSSAPDEIQH PHIKFSEWKF KLFRVRSFEK TPEEAQKEKK DSFEGKPSLE
QSPAVLDKAD GQKPVPTQPL LKAHPKFSKK FHDNEKARGK AIHQANLRHL CRICGNSFRA
DEHNRRYPVH GPVDGKTLGL LRKKEKRATS WPDLIAKVFR IDVKADVDSI HPTEFCHNCW
SIMHRKFSSA PCEVYFPRNV TMEWHPHTPS CDICNTARRG LKRKSLQPNL QLSKKLKTVL
DQARQARQHK RRAQARISSK DVMKKIANCS KIHLSTKLLA VDFPEHFVKS ISCQICEHIL
ADPVETNCKH VFCRVCILRC LKVMGSYCPS CRYPCFPTDL ESPVKSFLSV LNSLMVKCPA
KECNEEVSLE KYNHHISSHK ESKEIFVHIN KGGRPRQHLL SLTRRAQKHR LRELKLQVKA
FADKEEGGDV KSVCMTLFLL ALRARNEHRQ ADELEAIMQG KGSGLQPAVC LAIRVNTFLS
CSQYHKMYRT VKAITGRQIF QPLHALRNAE KVLLPGYHHF EWQPPLKNVS SSTDVGIIDG
LSGLSSSVDD YPVDTIAKRF RYDSALVSAL MDMEEDILEG MRSQDLDDYL NGPFTVVVKE
SCDGMGDVSE KHGSGPVVPE KAVRFSFTIM KITIAHSSQN VKVFEEAKPN SELCCKPLCL
MLADESDHET LTAILSPLIA EREAMKSSEL MLELGGILRT FKFIFRGTGY DEKLVREVEG
LEASGSVYIC TLCDATRLEA SQNLVFHSIT RSHAENLERY EVWRSNPYHE SVEELRDRVK
GVSAKPFIET VPSIDALHCD IGNAAEFYKI FQLEIGEVYK NPNASKEERK RWQATLDKHL
RKKMNLKPIM RMNGNFARKL MTKETVDAVC ELIPSEERHE ALRELMDLYL KMKPVWRSSC
PAKECPESLC QYSFNSQRFA ELLSTKFKYR YEGKITNYFH KTLAHVPEII ERDGSIGAWA
SEGNESGNKL FRRFRKMNAR QSKCYEMEDV LKHHWLYTSK YLQKFMNAHN ALKTSGFTMN
PQASLGDPLG IEDSLESQDS MEF
