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P21784 (RAG2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·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
Synonyms:Rag-2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

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. Ref.1 Ref.4 Ref.5 Ref.8 Ref.10 Ref.11

Subunit structure

Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Ref.5 Ref.6

Subcellular location

Nucleus.

Tissue specificity

Maturing lymphoid cells.

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). Ref.9 Ref.14

Disruption phenotype

Mice are viable but fail to produce mature B or T-lymphocytes. Very immature lymphoid cells are present in primary lymphoid organs. These cells do not rearrange their immunoglobulin or T-cell receptor loci. Ref.3

Sequence similarities

Belongs to the RAG2 family.

Contains 1 PHD-type zinc finger.

Ontologies

Keywords
   Biological processDNA recombination
   Cellular componentNucleus
   DomainZinc-finger
   LigandMetal-binding
Zinc
   Molecular functionChromatin regulator
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from mutant phenotype PubMed 1547488. Source: UniProtKB

B cell homeostatic proliferation

Inferred from mutant phenotype PubMed 9052834. Source: MGI

B cell lineage commitment

Inferred from mutant phenotype PubMed 8788039. Source: MGI

DNA recombination

Traceable author statement PubMed 12606021. Source: MGI

T cell differentiation

Inferred from mutant phenotype PubMed 11980719PubMed 14595002. Source: MGI

T cell differentiation in thymus

Inferred from mutant phenotype PubMed 1547488. Source: UniProtKB

T cell lineage commitment

Inferred from mutant phenotype PubMed 8788039. Source: MGI

V(D)J recombination

Inferred from mutant phenotype PubMed 1547488Ref.9. Source: UniProtKB

chromatin modification

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of organ growth

Inferred from mutant phenotype PubMed 9252127. Source: MGI

pre-B cell allelic exclusion

Inferred from mutant phenotype Ref.11. Source: UniProtKB

   Cellular_componentnucleus

Inferred by curator Ref.9. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: InterPro

chromatin binding

Inferred from direct assay Ref.14Ref.9. Source: UniProtKB

methylated histone residue binding

Inferred from direct assay Ref.14Ref.9. Source: UniProtKB

phosphatidylinositol binding

Inferred from direct assay Ref.9. Source: UniProtKB

phosphatidylinositol-3,4,5-trisphosphate binding

Inferred from direct assay Ref.13. Source: UniProtKB

phosphatidylinositol-3,4-bisphosphate binding

Inferred from direct assay Ref.13. Source: UniProtKB

phosphatidylinositol-3,5-bisphosphate binding

Inferred from direct assay Ref.13. Source: UniProtKB

phosphatidylinositol-4,5-bisphosphate binding

Inferred from direct assay Ref.13. Source: UniProtKB

zinc ion binding

Inferred from direct assay Ref.13Ref.14Ref.9. 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_0000167138

Regions

Zinc finger416 – 48469PHD-type; atypical
Compositional bias352 – 41059Asp/Glu-rich (acidic)

Sites

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

Experimental info

Mutagenesis1281D → N: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis1991E → Q: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis2021D → N: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis2801E → Q: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis3101D → N: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis3581D → N: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis3741D → N: Does not affect the endonuclease activity of the RAG complex. Ref.7
Mutagenesis4021Y → A: Reduced interaction with histones. Ref.8
Mutagenesis4031N → A: Reduced interaction with histones. Ref.8
Mutagenesis4061D → A: Reduced interaction with histones. Ref.8
Mutagenesis4071E → A: Reduced interaction with histones. Ref.8
Mutagenesis4081D → A: Induces a slight reduction in V(D)J recombination without affecting interaction with histones.
Mutagenesis4151Y → A: Abolishes binding to H3K4me3 without affecting phosphoinositide-binding. Ref.9
Mutagenesis4401K → A: Binds PtdIns(4,5)P2 at wild-type level. Ref.13
Mutagenesis4431M → A: Abolishes binding to H3K4me3 without affecting phosphoinositide-binding. Ref.9
Mutagenesis4451Y → A or D: Still binds H3K4me3 and H3R2me2 but with reduced affinity. Ref.14
Mutagenesis4531W → R: Abolishes binding to H3K4me3 without affecting phosphoinositide-binding. Impairs enzymatic activity of the RAG complex. Ref.9 Ref.10
Mutagenesis4641R → A: Leads to a strong reduction in PtdIns(4,5)P2-binding. Ref.13
Mutagenesis4681H → A: Leads to a strong reduction in PtdIns(4,5)P2-binding. Ref.13

Secondary structure

..................... 527
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P21784 [UniParc].

Last modified July 15, 1998. Version 2.
Checksum: 51086F95A4A664A7

FASTA52759,074
        10         20         30         40         50         60 
MSLQMVTVGH NIALIQPGFS LMNFDGQVFF FGQKGWPKRS CPTGVFHFDI KQNHLKLKPA 

        70         80         90        100        110        120 
IFSKDSCYLP PLRYPATCSY KGSIDSDKHQ YIIHGGKTPN NELSDKIYIM SVACKNNKKV 

       130        140        150        160        170        180 
TFRCTEKDLV GDVPEPRYGH SIDVVYSRGK SMGVLFGGRS YMPSTQRTTE KWNSVADCLP 

       190        200        210        220        230        240 
HVFLIDFEFG CATSYILPEL QDGLSFHVSI ARNDTVYILG GHSLASNIRP ANLYRIRVDL 

       250        260        270        280        290        300 
PLGTPAVNCT VLPGGISVSS AILTQTNNDE FVIVGGYQLE NQKRMVCSLV SLGDNTIEIS 

       310        320        330        340        350        360 
EMETPDWTSD IKHSKIWFGS NMGNGTIFLG IPGDNKQAMS EAFYFYTLRC SEEDLSEDQK 

       370        380        390        400        410        420 
IVSNSQTSTE DPGDSTPFED SEEFCFSAEA TSFDGDDEFD TYNEDDEDDE SVTGYWITCC 

       430        440        450        460        470        480 
PTCDVDINTW VPFYSTELNK PAMIYCSHGD GHWVHAQCMD LEERTLIHLS EGSNKYYCNE 

       490        500        510        520 
HVQIARALQT PKRNPPLQKP PMKSLHKKGS GKVLTPAKKS FLRRLFD 

« Hide

References

[1]"RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination."
Oettinger M.A., Schatz D.G., Gorka C., Baltimore D.
Science 248:1517-1523(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]Oettinger M.A., Schatz D.G., Gorka C., Baltimore D.
Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION TO 458.
[3]"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement."
Shinkai Y., Rathbun G., Lam K.P., Oltz E.M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A.M., Alt F.W.
Cell 68:855-867(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[4]"Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps."
McBlane J.F., van Gent D.C., Ramsden D.A., Romeo C., Cuomo C.A., Gellert M., Oettinger M.A.
Cell 83:387-395(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RAG1.
[5]"RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination."
Agrawal A., Schatz D.G.
Cell 89:43-53(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, IDENTIFICATION IN THE RAG COMPLEX.
[6]"Stimulation of V(D)J cleavage by high mobility group proteins."
van Gent D.C., Hiom K., Paull T.T., Gellert M.
EMBO J. 16:2665-2670(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN THE RAG COMPLEX.
[7]"Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination."
Landree M.A., Wibbenmeyer J.A., Roth D.B.
Genes Dev. 13:3059-3069(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ASP-128; GLU-199; ASP-202; GLU-280; ASP-310; ASP-358 AND ASP-374.
[8]"A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination."
West K.L., Singha N.C., De Ioannes P., Lacomis L., Erdjument-Bromage H., Tempst P., Cortes P.
Immunity 23:203-212(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, HISTONE-BINDING, MUTAGENESIS OF TYR-402; ASN-403; ASP-406 AND GLU-407.
[9]"RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination."
Matthews A.G., Kuo A.J., Ramon-Maiques S., Han S., Champagne K.S., Ivanov D., Gallardo M., Carney D., Cheung P., Ciccone D.N., Walter K.L., Utz P.J., Shi Y., Kutateladze T.G., Yang W., Gozani O., Oettinger M.A.
Nature 450:1106-1110(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN PHD-TYPE ZINC-FINGER, ZINC-BINDING, HISTONE-BINDING, MUTAGENESIS OF TYR-415; MET-443 AND TRP-453.
[10]"H3K4me3 stimulates the V(D)J RAG complex for both nicking and hairpinning in trans in addition to tethering in cis: implications for translocations."
Shimazaki N., Tsai A.G., Lieber M.R.
Mol. Cell 34:535-544(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF TRP-453.
[11]"RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci."
Hewitt S.L., Yin B., Ji Y., Chaumeil J., Marszalek K., Tenthorey J., Salvagiotto G., Steinel N., Ramsey L.B., Ghysdael J., Farrar M.A., Sleckman B.P., Schatz D.G., Busslinger M., Bassing C.H., Skok J.A.
Nat. Immunol. 10:655-664(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"Structure of the RAG1 nonamer binding domain with DNA reveals a dimer that mediates DNA synapsis."
Yin F.F., Bailey S., Innis C.A., Ciubotaru M., Kamtekar S., Steitz T.A., Schatz D.G.
Nat. Struct. Mol. Biol. 16:499-508(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RAG1.
[13]"A PHD finger motif in the C terminus of RAG2 modulates recombination activity."
Elkin S.K., Ivanov D., Ewalt M., Ferguson C.G., Hyberts S.G., Sun Z.Y., Prestwich G.D., Yuan J., Wagner G., Oettinger M.A., Gozani O.P.
J. Biol. Chem. 280:28701-28710(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 414-487 IN COMPLEX WITH ZINC, ZINC-BINDING, PHOSPHOINOSITIDE-BINDING, MUTAGENESIS OF LYS-440; ARG-464 AND HIS-468.
[14]"The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2."
Ramon-Maiques S., Kuo A.J., Carney D., Matthews A.G., Oettinger M.A., Gozani O., Yang W.
Proc. Natl. Acad. Sci. U.S.A. 104:18993-18998(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 414-487 IN COMPLEX WITH ZINC AND H3 PEPTIDE, DOMAIN PHD-TYPE ZINC-FINGER, ZINC-BINDING, HISTONE-BINDING, MUTAGENESIS OF TYR-445.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M64796 mRNA. Translation: AAB82302.1.
PIRA34852.
RefSeqNP_033046.1. NM_009020.3.
UniGeneMm.4988.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2JWONMR-A414-487[»]
2V83X-ray2.40A/B/C414-487[»]
2V85X-ray2.00A/B414-487[»]
2V86X-ray2.05A/B414-487[»]
2V87X-ray1.80A/B414-487[»]
2V88X-ray2.00A/B414-487[»]
2V89X-ray1.10A/B414-487[»]
ProteinModelPortalP21784.
SMRP21784. Positions 130-226, 414-487.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid202575. 1 interaction.
DIPDIP-46179N.
IntActP21784. 3 interactions.
MINTMINT-8384500.

PTM databases

PhosphoSiteP21784.

Proteomic databases

PRIDEP21784.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000044031; ENSMUSP00000038204; ENSMUSG00000032864.
ENSMUST00000111227; ENSMUSP00000106858; ENSMUSG00000032864.
GeneID19374.
KEGGmmu:19374.
UCSCuc008lhj.1. mouse.

Organism-specific databases

CTD5897.
MGIMGI:97849. Rag2.

Phylogenomic databases

eggNOGNOG39310.
HOGENOMHOG000237346.
HOVERGENHBG006694.
InParanoidP21784.
KOK10988.
OMAFGQKGWP.
OrthoDBEOG73804B.
PhylomeDBP21784.
TreeFamTF331236.

Gene expression databases

BgeeP21784.
CleanExMM_RAG2.
GenevestigatorP21784.

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

EvolutionaryTraceP21784.
NextBio296467.
PROP21784.
SOURCESearch...

Entry information

Entry nameRAG2_MOUSE
AccessionPrimary (citable) accession number: P21784
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: July 15, 1998
Last modified: April 16, 2014
This is version 118 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot