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P55895 (RAG2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 123. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
V(D)J recombination-activating protein 2

Short name=RAG-2
Gene names
Name:RAG2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length527 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. DNA cleavage by the RAG complex occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3 By similarity.

Subunit structure

Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2 By similarity.

Subcellular location

Nucleus By similarity.

Tissue specificity

Cells of the B- and T-lymphocyte lineages.

Domain

The atypical PHD-type zinc finger recognizes and binds histone H3 trimethylated on 'Lys-4' (H3K4me3). The presence Tyr-445 instead of a carboxylate in classical PHD-type zinc fingers results in an enhanced binding to H3K4me3 in presence of dimethylated on 'Arg-2' (H3R2me2) rather than inhibited. The atypical PHD-type zinc finger also binds various phosphoinositides, such as phosphatidylinositol 3,4-bisphosphate binding (PtdIns(3,4)P2), phosphatidylinositol 3,5-bisphosphate binding (PtdIns(3,5)P2), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate binding (PtdIns(3,4,5)P3) By similarity.

Involvement in disease

Combined cellular and humoral immune defects with granulomas (CHIDG) [MIM:233650]: Immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. Other characteristics include hypogammaglobulinemia, a diminished number of T and B-cells, and sparse thymic tissue on ultrasonography.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8

Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID) [MIM:601457]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.7

Omenn syndrome (OS) [MIM:603554]: Severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7

Sequence similarities

Belongs to the RAG2 family.

Contains 1 PHD-type zinc finger.

Ontologies

Keywords
   Biological processDNA recombination
   Cellular componentNucleus
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
SCID
   DomainZinc-finger
   LigandMetal-binding
Zinc
   Molecular functionChromatin regulator
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

B cell homeostatic proliferation

Inferred from electronic annotation. Source: Ensembl

B cell lineage commitment

Inferred from electronic annotation. Source: Ensembl

T cell differentiation in thymus

Inferred from sequence or structural similarity. Source: UniProtKB

T cell lineage commitment

Inferred from electronic annotation. Source: Ensembl

V(D)J recombination

Inferred from sequence or structural similarity. Source: UniProtKB

chromatin modification

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of organ growth

Inferred from electronic annotation. Source: Ensembl

pre-B cell allelic exclusion

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentnucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: InterPro

chromatin binding

Inferred from sequence or structural similarity. Source: UniProtKB

methylated histone binding

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol binding

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol-3,4,5-trisphosphate binding

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol-3,4-bisphosphate binding

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol-3,5-bisphosphate binding

Inferred from sequence or structural similarity. Source: UniProtKB

phosphatidylinositol-4,5-bisphosphate binding

Inferred from sequence or structural similarity. Source: UniProtKB

zinc ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 527527V(D)J recombination-activating protein 2
PRO_0000167137

Regions

Zinc finger416 – 48469PHD-type; atypical

Sites

Metal binding4191Zinc 1 By similarity
Metal binding4231Zinc 1 By similarity
Metal binding4461Zinc 2 By similarity
Metal binding4521Zinc 2 By similarity
Metal binding4551Zinc 1 By similarity
Metal binding4581Zinc 1 By similarity
Metal binding4781Zinc 2 By similarity
Metal binding4811Zinc 2 By similarity

Natural variations

Natural variant411C → W in OS. Ref.7
VAR_008895
Natural variant771T → N in CHIDG; reduced recombination activity. Ref.8
VAR_045960
Natural variant2291R → Q in T(-)B(-)NK(+) SCID. Ref.6
VAR_005570
Natural variant2851M → R in OS. Ref.7
VAR_008896
Natural variant2931E → G.
Corresponds to variant rs16929093 [ dbSNP | Ensembl ].
VAR_045961
Natural variant4511G → A in CHIDG; reduced recombination activity. Ref.8
VAR_045962
Natural variant4781C → Y in T(-)B(-)NK(+) SCID. Ref.6
VAR_005571

Experimental info

Sequence conflict1541V → A in AAH22397. Ref.4
Sequence conflict3221M → T in AAH22397. Ref.4

Sequences

Sequence LengthMass (Da)Tools
P55895 [UniParc].

Last modified November 1, 1997. Version 1.
Checksum: 1CC4D0F88635BA87

FASTA52759,241
        10         20         30         40         50         60 
MSLQMVTVSN NIALIQPGFS LMNFDGQVFF FGQKGWPKRS CPTGVFHLDV KHNHVKLKPT 

        70         80         90        100        110        120 
IFSKDSCYLP PLRYPATCTF KGSLESEKHQ YIIHGGKTPN NEVSDKIYVM SIVCKNNKKV 

       130        140        150        160        170        180 
TFRCTEKDLV GDVPEARYGH SINVVYSRGK SMGVLFGGRS YMPSTHRTTE KWNSVADCLP 

       190        200        210        220        230        240 
CVFLVDFEFG CATSYILPEL QDGLSFHVSI AKNDTIYILG GHSLANNIRP ANLYRIRVDL 

       250        260        270        280        290        300 
PLGSPAVNCT VLPGGISVSS AILTQTNNDE FVIVGGYQLE NQKRMICNII SLEDNKIEIR 

       310        320        330        340        350        360 
EMETPDWTPD IKHSKIWFGS NMGNGTVFLG IPGDNKQVVS EGFYFYMLKC AEDDTNEEQT 

       370        380        390        400        410        420 
TFTNSQTSTE DPGDSTPFED SEEFCFSAEA NSFDGDDEFD TYNEDDEEDE SETGYWITCC 

       430        440        450        460        470        480 
PTCDVDINTW VPFYSTELNK PAMIYCSHGD GHWVHAQCMD LAERTLIHLS AGSNKYYCNE 

       490        500        510        520 
HVEIARALHT PQRVLPLKKP PMKSLRKKGS GKILTPAKKS FLRRLFD 

« Hide

References

« Hide 'large scale' references
[1]"Sequence and chromosome assignment to 11p13-p12 of human RAG genes."
Ichihara Y., Hirai M., Kurosawa Y.
Immunol. Lett. 33:277-284(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Placenta.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Thymus.
[3]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Testis.
[5]"Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression."
Bories J.C., Cayuela J.-M., Loiseau P., Sigaux F.
Blood 78:2053-2061(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 318-411.
[6]"RAG mutations in human B cell-negative SCID."
Schwarz K., Gauss G.H., Ludwig L., Pannicke U., Li Z., Linder D., Friedrich W., Seger R.A., Hansen-Hagge T.E., Desiderio S., Lieber M.R., Bartram C.R.
Science 274:97-99(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS T(-)B(-)NK(+) SCID GLN-229 AND TYR-478.
[7]"Partial V(D)J recombination activity leads to Omenn syndrome."
Villa A., Santagata S., Bozzi F., Giliani S., Frattini A., Imberti L., Gatta L.B., Ochs H.D., Schwarz K., Notarangelo L.D., Vezzoni P., Spanopoulou E.
Cell 93:885-896(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS OS TRP-41 AND ARG-285.
[8]"An immunodeficiency disease with RAG mutations and granulomas."
Schuetz C., Huck K., Gudowius S., Megahed M., Feyen O., Hubner B., Schneider D.T., Manfras B., Pannicke U., Willemze R., Knuechel R., Goebel U., Schulz A., Borkhardt A., Friedrich W., Schwarz K., Niehues T.
N. Engl. J. Med. 358:2030-2038(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CHIDG ASN-77 AND ALA-451, CHARACTERIZATION OF VARIANTS CHIDG ASN-77 AND ALA-451.
+Additional computationally mapped references.

Web resources

RAG2base

RAG2 deficiency database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M94633 Genomic DNA. No translation available.
AK292664 mRNA. Translation: BAF85353.1.
CH471064 Genomic DNA. Translation: EAW68117.1.
BC022397 mRNA. Translation: AAH22397.1.
CCDSCCDS7903.1.
RefSeqNP_000527.2. NM_000536.3.
NP_001230714.1. NM_001243785.1.
NP_001230715.1. NM_001243786.1.
UniGeneHs.714519.

3D structure databases

ProteinModelPortalP55895.
SMRP55895. Positions 414-486.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111833. 6 interactions.
STRING9606.ENSP00000308620.

PTM databases

PhosphoSiteP55895.

Polymorphism databases

DMDM2498830.

Proteomic databases

PaxDbP55895.
PRIDEP55895.

Protocols and materials databases

DNASU5897.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000311485; ENSP00000308620; ENSG00000175097.
GeneID5897.
KEGGhsa:5897.
UCSCuc001mwv.4. human.

Organism-specific databases

CTD5897.
GeneCardsGC11M036613.
H-InvDBHIX0009568.
HGNCHGNC:9832. RAG2.
MIM179616. gene.
233650. phenotype.
601457. phenotype.
603554. phenotype.
neXtProtNX_P55895.
Orphanet157949. Combined immunodeficiency with skin granulomas.
39041. Omenn syndrome.
331206. Severe combined immunodeficiency due to complete RAG1/2 deficiency.
PharmGKBPA34186.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG39310.
HOGENOMHOG000237346.
HOVERGENHBG006694.
InParanoidP55895.
KOK10988.
OMAFGQKGWP.
OrthoDBEOG73804B.
PhylomeDBP55895.
TreeFamTF331236.

Gene expression databases

BgeeP55895.
CleanExHS_RAG2.
GenevestigatorP55895.

Family and domain databases

Gene3D2.120.10.80. 1 hit.
InterProIPR011043. Gal_Oxase/kelch_b-propeller.
IPR015915. Kelch-typ_b-propeller.
IPR004321. RAG2.
IPR025162. RAG2_PHD.
IPR011011. Znf_FYVE_PHD.
[Graphical view]
PANTHERPTHR10960. PTHR10960. 1 hit.
PfamPF03089. RAG2. 1 hit.
PF13341. RAG2_PHD. 1 hit.
[Graphical view]
SUPFAMSSF50965. SSF50965. 1 hit.
SSF57903. SSF57903. 1 hit.
ProtoNetSearch...

Other

GenomeRNAi5897.
NextBio22938.
PROP55895.
SOURCESearch...

Entry information

Entry nameRAG2_HUMAN
AccessionPrimary (citable) accession number: P55895
Secondary accession number(s): A8K9E9, Q8TBL4
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: July 9, 2014
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM