RAG2_HUMAN
ID RAG2_HUMAN Reviewed; 527 AA.
AC P55895; A8K9E9; Q8TBL4;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=V(D)J recombination-activating protein 2;
DE Short=RAG-2;
GN Name=RAG2;
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 [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=1428003; DOI=10.1016/0165-2478(92)90073-w;
RA Ichihara Y., Hirai M., Kurosawa Y.;
RT "Sequence and chromosome assignment to 11p13-p12 of human RAG genes.";
RL Immunol. Lett. 33:277-284(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thymus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 NUCLEOTIDE SEQUENCE [MRNA] OF 318-411.
RX PubMed=1832998;
RA Bories J.C., Cayuela J.-M., Loiseau P., Sigaux F.;
RT "Expression of human recombination activating genes (RAG1 and RAG2) in
RT neoplastic lymphoid cells: correlation with cell differentiation and
RT antigen receptor expression.";
RL Blood 78:2053-2061(1991).
RN [6]
RP VARIANTS T(-)B(-)NK(+) SCID GLN-229 AND TYR-478.
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 [7]
RP VARIANTS OS TRP-41 AND ARG-285.
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 [8]
RP VARIANTS CHIDG ASN-77 AND ALA-451, AND CHARACTERIZATION OF VARIANTS CHIDG
RP ASN-77 AND ALA-451.
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).
CC -!- FUNCTION: Core component of the RAG complex, a multiprotein complex
CC that mediates the DNA cleavage phase during V(D)J recombination. V(D)J
CC recombination assembles a diverse repertoire of immunoglobulin and T-
CC cell receptor genes in developing B and T-lymphocytes through
CC rearrangement of different V (variable), in some cases D (diversity),
CC and J (joining) gene segments. DNA cleavage by the RAG complex occurs
CC in 2 steps: a first nick is introduced in the top strand immediately
CC upstream of the heptamer, generating a 3'-hydroxyl group that can
CC attack the 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 the RAG complex, RAG2 is not the
CC catalytic component but is required for all known catalytic activities
CC mediated by RAG1. It probably acts as a sensor of chromatin state that
CC recruits the RAG complex to H3K4me3 (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Component of the RAG complex composed of core components RAG1
CC and RAG2, and associated component HMGB1 or HMGB2. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Cells of the B- and T-lymphocyte lineages.
CC -!- DOMAIN: The atypical PHD-type zinc finger recognizes and binds histone
CC H3 trimethylated on 'Lys-4' (H3K4me3). The presence Tyr-445 instead of
CC a carboxylate in classical PHD-type zinc fingers results in an enhanced
CC binding to H3K4me3 in presence of dimethylated on 'Arg-2' (H3R2me2)
CC rather than inhibited. The atypical PHD-type zinc finger also binds
CC various phosphoinositides, such as phosphatidylinositol 3,4-
CC bisphosphate binding (PtdIns(3,4)P2), phosphatidylinositol 3,5-
CC bisphosphate binding (PtdIns(3,5)P2), phosphatidylinositol 4,5-
CC bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,4,5-
CC trisphosphate binding (PtdIns(3,4,5)P3) (By similarity). {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:8810255}. Note=The disease is caused
CC by variants affecting the gene represented 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:9630231}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the RAG2 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=RAG2base; Note=RAG2 deficiency database;
CC URL="http://structure.bmc.lu.se/idbase/RAG2base/";
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DR EMBL; M94633; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK292664; BAF85353.1; -; mRNA.
DR EMBL; CH471064; EAW68117.1; -; Genomic_DNA.
DR EMBL; BC022397; AAH22397.1; -; mRNA.
DR CCDS; CCDS7903.1; -.
DR RefSeq; NP_000527.2; NM_000536.3.
DR RefSeq; NP_001230714.1; NM_001243785.1.
DR RefSeq; NP_001230715.1; NM_001243786.1.
DR AlphaFoldDB; P55895; -.
DR SMR; P55895; -.
DR BioGRID; 111833; 17.
DR CORUM; P55895; -.
DR STRING; 9606.ENSP00000478672; -.
DR iPTMnet; P55895; -.
DR PhosphoSitePlus; P55895; -.
DR BioMuta; RAG2; -.
DR DMDM; 2498830; -.
DR jPOST; P55895; -.
DR PaxDb; P55895; -.
DR PRIDE; P55895; -.
DR Antibodypedia; 26023; 274 antibodies from 33 providers.
DR DNASU; 5897; -.
DR Ensembl; ENST00000311485.8; ENSP00000308620.4; ENSG00000175097.8.
DR Ensembl; ENST00000618712.4; ENSP00000478672.1; ENSG00000175097.8.
DR GeneID; 5897; -.
DR KEGG; hsa:5897; -.
DR MANE-Select; ENST00000311485.8; ENSP00000308620.4; NM_000536.4; NP_000527.2.
DR UCSC; uc001mwv.5; human.
DR CTD; 5897; -.
DR DisGeNET; 5897; -.
DR GeneCards; RAG2; -.
DR HGNC; HGNC:9832; RAG2.
DR HPA; ENSG00000175097; Tissue enriched (lymphoid).
DR MalaCards; RAG2; -.
DR MIM; 179616; gene.
DR MIM; 233650; phenotype.
DR MIM; 601457; phenotype.
DR MIM; 603554; phenotype.
DR neXtProt; NX_P55895; -.
DR OpenTargets; ENSG00000175097; -.
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; PA34186; -.
DR VEuPathDB; HostDB:ENSG00000175097; -.
DR eggNOG; ENOG502QVKU; Eukaryota.
DR GeneTree; ENSGT00390000012559; -.
DR HOGENOM; CLU_516740_0_0_1; -.
DR InParanoid; P55895; -.
DR OMA; WNSVVDC; -.
DR OrthoDB; 687724at2759; -.
DR PhylomeDB; P55895; -.
DR TreeFam; TF331236; -.
DR PathwayCommons; P55895; -.
DR Reactome; R-HSA-1266695; Interleukin-7 signaling.
DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR SignaLink; P55895; -.
DR SIGNOR; P55895; -.
DR BioGRID-ORCS; 5897; 13 hits in 1076 CRISPR screens.
DR ChiTaRS; RAG2; human.
DR GenomeRNAi; 5897; -.
DR Pharos; P55895; Tbio.
DR PRO; PR:P55895; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P55895; protein.
DR Bgee; ENSG00000175097; Expressed in thymus and 97 other tissues.
DR ExpressionAtlas; P55895; baseline and differential.
DR Genevisible; P55895; HS.
DR GO; GO:0097519; C:DNA recombinase complex; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0035064; F:methylated histone binding; ISS:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; ISS:UniProtKB.
DR GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; ISS:UniProtKB.
DR GO; GO:0043325; F:phosphatidylinositol-3,4-bisphosphate binding; ISS:UniProtKB.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; ISS:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB.
DR GO; GO:0002358; P:B cell homeostatic proliferation; IEA:Ensembl.
DR GO; GO:0002326; P:B cell lineage commitment; IEA:Ensembl.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:1904155; P:DN2 thymocyte differentiation; IEA:Ensembl.
DR GO; GO:0002313; P:mature B cell differentiation involved in immune response; IEA:Ensembl.
DR GO; GO:0033085; P:negative regulation of T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0046622; P:positive regulation of organ growth; IEA:Ensembl.
DR GO; GO:0002331; P:pre-B cell allelic exclusion; ISS:UniProtKB.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB.
DR GO; GO:0002360; P:T cell lineage commitment; IEA:Ensembl.
DR GO; GO:0033151; P:V(D)J recombination; ISS:UniProtKB.
DR CDD; cd15569; PHD_RAG2; 1.
DR Gene3D; 2.120.10.80; -; 1.
DR InterPro; IPR011043; Gal_Oxase/kelch_b-propeller.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR004321; RAG2.
DR InterPro; IPR025162; RAG2_PHD.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR PANTHER; PTHR10960; PTHR10960; 1.
DR Pfam; PF03089; RAG2; 1.
DR Pfam; PF13341; RAG2_PHD; 1.
DR SUPFAM; SSF50965; SSF50965; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
PE 1: Evidence at protein level;
KW Chromatin regulator; Disease variant; DNA recombination; Metal-binding;
KW Nucleus; Reference proteome; SCID; Zinc; Zinc-finger.
FT CHAIN 1..527
FT /note="V(D)J recombination-activating protein 2"
FT /id="PRO_0000167137"
FT ZN_FING 416..484
FT /note="PHD-type; atypical"
FT REGION 357..380
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 357..374
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 419
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 423
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 446
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 452
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 455
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 458
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 478
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 481
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT VARIANT 41
FT /note="C -> W (in OS; dbSNP:rs121917895)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008895"
FT VARIANT 77
FT /note="T -> N (in CHIDG; reduced recombination activity;
FT dbSNP:rs121918574)"
FT /evidence="ECO:0000269|PubMed:18463379"
FT /id="VAR_045960"
FT VARIANT 229
FT /note="R -> Q (in T(-)B(-)NK(+) SCID; dbSNP:rs121917894)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_005570"
FT VARIANT 285
FT /note="M -> R (in OS; dbSNP:rs121917896)"
FT /evidence="ECO:0000269|PubMed:9630231"
FT /id="VAR_008896"
FT VARIANT 293
FT /note="E -> G (in dbSNP:rs16929093)"
FT /id="VAR_045961"
FT VARIANT 451
FT /note="G -> A (in CHIDG; reduced recombination activity;
FT dbSNP:rs121918575)"
FT /evidence="ECO:0000269|PubMed:18463379"
FT /id="VAR_045962"
FT VARIANT 478
FT /note="C -> Y (in T(-)B(-)NK(+) SCID; dbSNP:rs121918573)"
FT /evidence="ECO:0000269|PubMed:8810255"
FT /id="VAR_005571"
FT CONFLICT 154
FT /note="V -> A (in Ref. 4; AAH22397)"
FT /evidence="ECO:0000305"
FT CONFLICT 322
FT /note="M -> T (in Ref. 4; AAH22397)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 527 AA; 59241 MW; 1CC4D0F88635BA87 CRC64;
MSLQMVTVSN NIALIQPGFS LMNFDGQVFF FGQKGWPKRS CPTGVFHLDV KHNHVKLKPT
IFSKDSCYLP PLRYPATCTF KGSLESEKHQ YIIHGGKTPN NEVSDKIYVM SIVCKNNKKV
TFRCTEKDLV GDVPEARYGH SINVVYSRGK SMGVLFGGRS YMPSTHRTTE KWNSVADCLP
CVFLVDFEFG CATSYILPEL QDGLSFHVSI AKNDTIYILG GHSLANNIRP ANLYRIRVDL
PLGSPAVNCT VLPGGISVSS AILTQTNNDE FVIVGGYQLE NQKRMICNII SLEDNKIEIR
EMETPDWTPD IKHSKIWFGS NMGNGTVFLG IPGDNKQVVS EGFYFYMLKC AEDDTNEEQT
TFTNSQTSTE DPGDSTPFED SEEFCFSAEA NSFDGDDEFD TYNEDDEEDE SETGYWITCC
PTCDVDINTW VPFYSTELNK PAMIYCSHGD GHWVHAQCMD LAERTLIHLS AGSNKYYCNE
HVEIARALHT PQRVLPLKKP PMKSLRKKGS GKILTPAKKS FLRRLFD
