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Protein

V(D)J recombination-activating protein 2

Gene

RAG2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi419Zinc 1By similarity1
Metal bindingi423Zinc 1By similarity1
Metal bindingi446Zinc 2By similarity1
Metal bindingi452Zinc 2By similarity1
Metal bindingi455Zinc 1By similarity1
Metal bindingi458Zinc 1By similarity1
Metal bindingi478Zinc 2By similarity1
Metal bindingi481Zinc 2By similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri416 – 484PHD-type; atypicalAdd BLAST69

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionChromatin regulator
Biological processDNA recombination
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-1266695 Interleukin-7 signaling
R-HSA-5687128 MAPK6/MAPK4 signaling
SIGNORiP55895

Names & Taxonomyi

Protein namesi
Recommended name:
V(D)J recombination-activating protein 2
Short name:
RAG-2
Gene namesi
Name:RAG2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000175097.7
HGNCiHGNC:9832 RAG2
MIMi179616 gene
neXtProtiNX_P55895

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Combined cellular and humoral immune defects with granulomas (CHIDG)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionImmunodeficiency 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.
See also OMIM:233650
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04596077T → N in CHIDG; reduced recombination activity. 1 PublicationCorresponds to variant dbSNP:rs121918574Ensembl.1
Natural variantiVAR_045962451G → A in CHIDG; reduced recombination activity. 1 PublicationCorresponds to variant dbSNP:rs121918575Ensembl.1
Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:601457
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_005570229R → Q in T(-)B(-)NK(+) SCID. 1 PublicationCorresponds to variant dbSNP:rs121917894Ensembl.1
Natural variantiVAR_005571478C → Y in T(-)B(-)NK(+) SCID. 1 PublicationCorresponds to variant dbSNP:rs121918573Ensembl.1
Omenn syndrome (OS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSevere immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels.
See also OMIM:603554
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00889541C → W in OS. 1 PublicationCorresponds to variant dbSNP:rs121917895Ensembl.1
Natural variantiVAR_008896285M → R in OS. 1 PublicationCorresponds to variant dbSNP:rs121917896Ensembl.1

Keywords - Diseasei

Disease mutation, SCID

Organism-specific databases

DisGeNETi5897
MalaCardsiRAG2
MIMi233650 phenotype
601457 phenotype
603554 phenotype
OpenTargetsiENSG00000175097
Orphaneti157949 Combined immunodeficiency with skin granulomas
39041 Omenn syndrome
331206 Severe combined immunodeficiency due to complete RAG1/2 deficiency
PharmGKBiPA34186

Polymorphism and mutation databases

BioMutaiRAG2
DMDMi2498830

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001671371 – 527V(D)J recombination-activating protein 2Add BLAST527

Proteomic databases

PaxDbiP55895
PeptideAtlasiP55895
PRIDEiP55895

PTM databases

iPTMnetiP55895
PhosphoSitePlusiP55895

Expressioni

Tissue specificityi

Cells of the B- and T-lymphocyte lineages.

Gene expression databases

BgeeiENSG00000175097
CleanExiHS_RAG2
ExpressionAtlasiP55895 baseline and differential
GenevisibleiP55895 HS

Interactioni

Subunit structurei

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi111833, 5 interactors
CORUMiP55895
STRINGi9606.ENSP00000308620

Structurei

3D structure databases

ProteinModelPortaliP55895
SMRiP55895
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domaini

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).By similarity

Sequence similaritiesi

Belongs to the RAG2 family.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri416 – 484PHD-type; atypicalAdd BLAST69

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IJ5S Eukaryota
ENOG4110081 LUCA
GeneTreeiENSGT00390000012559
HOGENOMiHOG000237346
HOVERGENiHBG006694
InParanoidiP55895
KOiK10988
OMAiFGQKGWP
OrthoDBiEOG091G052K
PhylomeDBiP55895
TreeFamiTF331236

Family and domain databases

CDDicd15569 PHD_RAG2, 1 hit
Gene3Di2.120.10.80, 1 hit
InterProiView protein in InterPro
IPR011043 Gal_Oxase/kelch_b-propeller
IPR015915 Kelch-typ_b-propeller
IPR004321 RAG2
IPR025162 RAG2_PHD
IPR011011 Znf_FYVE_PHD
PANTHERiPTHR10960 PTHR10960, 1 hit
PfamiView protein in Pfam
PF03089 RAG2, 1 hit
PF13341 RAG2_PHD, 1 hit
SUPFAMiSSF50965 SSF50965, 1 hit
SSF57903 SSF57903, 1 hit

Sequencei

Sequence statusi: Complete.

P55895-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSLQMVTVSN NIALIQPGFS LMNFDGQVFF FGQKGWPKRS CPTGVFHLDV
60 70 80 90 100
KHNHVKLKPT IFSKDSCYLP PLRYPATCTF KGSLESEKHQ YIIHGGKTPN
110 120 130 140 150
NEVSDKIYVM SIVCKNNKKV TFRCTEKDLV GDVPEARYGH SINVVYSRGK
160 170 180 190 200
SMGVLFGGRS YMPSTHRTTE KWNSVADCLP CVFLVDFEFG CATSYILPEL
210 220 230 240 250
QDGLSFHVSI AKNDTIYILG GHSLANNIRP ANLYRIRVDL PLGSPAVNCT
260 270 280 290 300
VLPGGISVSS AILTQTNNDE FVIVGGYQLE NQKRMICNII SLEDNKIEIR
310 320 330 340 350
EMETPDWTPD IKHSKIWFGS NMGNGTVFLG IPGDNKQVVS EGFYFYMLKC
360 370 380 390 400
AEDDTNEEQT TFTNSQTSTE DPGDSTPFED SEEFCFSAEA NSFDGDDEFD
410 420 430 440 450
TYNEDDEEDE SETGYWITCC PTCDVDINTW VPFYSTELNK PAMIYCSHGD
460 470 480 490 500
GHWVHAQCMD LAERTLIHLS AGSNKYYCNE HVEIARALHT PQRVLPLKKP
510 520
PMKSLRKKGS GKILTPAKKS FLRRLFD
Length:527
Mass (Da):59,241
Last modified:November 1, 1997 - v1
Checksum:i1CC4D0F88635BA87
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti154V → A in AAH22397 (PubMed:15489334).Curated1
Sequence conflicti322M → T in AAH22397 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00889541C → W in OS. 1 PublicationCorresponds to variant dbSNP:rs121917895Ensembl.1
Natural variantiVAR_04596077T → N in CHIDG; reduced recombination activity. 1 PublicationCorresponds to variant dbSNP:rs121918574Ensembl.1
Natural variantiVAR_005570229R → Q in T(-)B(-)NK(+) SCID. 1 PublicationCorresponds to variant dbSNP:rs121917894Ensembl.1
Natural variantiVAR_008896285M → R in OS. 1 PublicationCorresponds to variant dbSNP:rs121917896Ensembl.1
Natural variantiVAR_045961293E → G. Corresponds to variant dbSNP:rs16929093Ensembl.1
Natural variantiVAR_045962451G → A in CHIDG; reduced recombination activity. 1 PublicationCorresponds to variant dbSNP:rs121918575Ensembl.1
Natural variantiVAR_005571478C → Y in T(-)B(-)NK(+) SCID. 1 PublicationCorresponds to variant dbSNP:rs121918573Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M94633 Genomic DNA No translation available.
AK292664 mRNA Translation: BAF85353.1
CH471064 Genomic DNA Translation: EAW68117.1
BC022397 mRNA Translation: AAH22397.1
CCDSiCCDS7903.1
RefSeqiNP_000527.2, NM_000536.3
NP_001230714.1, NM_001243785.1
NP_001230715.1, NM_001243786.1
UniGeneiHs.714519

Genome annotation databases

EnsembliENST00000311485; ENSP00000308620; ENSG00000175097
ENST00000618712; ENSP00000478672; ENSG00000175097
GeneIDi5897
KEGGihsa:5897
UCSCiuc001mwv.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiRAG2_HUMAN
AccessioniPrimary (citable) accession number: P55895
Secondary accession number(s): A8K9E9, Q8TBL4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: April 25, 2018
This is version 149 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
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Main funding by: National Institutes of Health