P55895 (RAG2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
V(D)J recombination-activating protein 2
Short name=RAG-2

Gene names

Name:

RAG2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	527 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	DNA recombination
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation SCID
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Chromatin regulator
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell homeostatic proliferation Inferred from electronic annotation. Source: Compara B cell lineage commitment Inferred from electronic annotation. Source: Compara T cell differentiation in thymus Inferred from sequence or structural similarity. Source: UniProtKB T cell lineage commitment Inferred from electronic annotation. Source: Compara 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: Compara pre-B cell allelic exclusion Inferred from sequence or structural similarity. Source: UniProtKB somatic diversification of immunoglobulins Non-traceable author statement. Source: UniProtKB
Cellular_component	nucleus Non-traceable author statement. Source: UniProtKB
Molecular_function	DNA binding Non-traceable author statement. Source: UniProtKB chromatin binding Inferred from sequence or structural similarity. Source: UniProtKB endonuclease activity Non-traceable author statement. Source: UniProtKB methylated histone residue 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 527	527	V(D)J recombination-activating protein 2		PRO_0000167137
Regions
	Zinc finger	416 – 484	69	PHD-type; atypical
Sites
	Metal binding	419	1	Zinc 1 By similarity
	Metal binding	423	1	Zinc 1 By similarity
	Metal binding	446	1	Zinc 2 By similarity
	Metal binding	452	1	Zinc 2 By similarity
	Metal binding	455	1	Zinc 1 By similarity
	Metal binding	458	1	Zinc 1 By similarity
	Metal binding	478	1	Zinc 2 By similarity
	Metal binding	481	1	Zinc 2 By similarity
Natural variations
	Natural variant	41	1	C → W in OS. Ref.7		VAR_008895
	Natural variant	77	1	T → N in CHIDG; reduced recombination activity. Ref.8		VAR_045960
	Natural variant	229	1	R → Q in T(-)B(-)NK(+) SCID. Ref.6		VAR_005570
	Natural variant	285	1	M → R in OS. Ref.7		VAR_008896
	Natural variant	293	1	E → G. Corresponds to variant rs16929093 [ dbSNP | Ensembl ].		VAR_045961
	Natural variant	451	1	G → A in CHIDG; reduced recombination activity. Ref.8		VAR_045962
	Natural variant	478	1	C → Y in T(-)B(-)NK(+) SCID. Ref.6		VAR_005571
Experimental info
	Sequence conflict	154	1	V → A in AAH22397. Ref.4
	Sequence conflict	322	1	M → T in AAH22397. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	P55895 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: 1CC4D0F88635BA87	FASTA	527	59,241
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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

GeneReviews

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.
IPI	IPI00299162.
RefSeq	NP_000527.2. NM_000536.3. NP_001230714.1. NM_001243785.1. NP_001230715.1. NM_001243786.1.
UniGene	Hs.714519.
3D structure databases
ProteinModelPortal	P55895.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000308620.
PTM databases
PhosphoSite	P55895.
Polymorphism databases
DMDM	2498830.
Proteomic databases
PaxDb	P55895.
PRIDE	P55895.
Protocols and materials databases
DNASU	5897.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000311485; ENSP00000308620; ENSG00000175097.
GeneID	5897.
KEGG	hsa:5897.
UCSC	uc001mwv.4. human.
Organism-specific databases
CTD	5897.
GeneCards	GC11M036613.
H-InvDB	HIX0009568.
HGNC	HGNC:9832. RAG2.
MIM	179616. gene. 233650. phenotype. 601457. phenotype. 603554. phenotype.
neXtProt	NX_P55895.
Orphanet	39041. Omenn syndrome. 275. Severe combined immunodeficiency due to DCLRE1C deficiency. 157949. Severe combined immunodeficiency with skin granulomas.
PharmGKB	PA34186.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG39310.
HOGENOM	HOG000237346.
HOVERGEN	HBG006694.
InParanoid	P55895.
KO	K10988.
OMA	GHWVHAQ.
OrthoDB	EOG44XJGJ.
PhylomeDB	P55895.
Gene expression databases
ArrayExpress	P55895.
Bgee	P55895.
CleanEx	HS_RAG2.
Genevestigator	P55895.
GermOnline	ENSG00000175097. Homo sapiens.
Family and domain databases
Gene3D	2.120.10.80. 1 hit.
InterPro	IPR011043. Gal_Oxase/kelch_b-propeller. IPR015915. Kelch-typ_b-propeller. IPR004321. RAG2. IPR025162. RAG2_PHD. [Graphical view]
PANTHER	PTHR10960. PTHR10960. 1 hit.
Pfam	PF03089. RAG2. 1 hit. PF13341. RAG2_PHD. 1 hit. [Graphical view]
SUPFAM	SSF50965. Gal_oxid_central. 1 hit.
PROSITE	PS01359. ZF_PHD_1. False negative. PS50016. ZF_PHD_2. False negative. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	5897.
NextBio	22938.
SOURCE	Search...

Entry information

Entry name

RAG2_HUMAN

Accession

Primary (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:	May 29, 2013
This is version 112 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.