Q9GZX7 (AICDA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Activation-induced cytidine deaminase
EC=3.5.4.5

Alternative name(s):
Cytidine aminohydrolase

Gene names

Name:	AICDA
Synonyms:	AID

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	198 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Single-stranded DNA-specific cytidine deaminase. Involved in somatic hypermutation, gene conversion, and class-switch recombination in B-lymphocytes. Required for several crucial steps of B-cell terminal differentiation necessary for efficient antibody responses. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Ref.7 Ref.8 Ref.9
Catalytic activity	Cytidine + H2O = uridine + NH3.
Cofactor	Zinc By similarity.
Subunit structure	Interacts with CTNNBL1; the interaction is important for the immunoglobulin switch activity of AICDA. Interacts (via its NLS) with KPNA1. Interacts with PKA/PRKACA and PRKAR1A/PKR1. Ref.6 Ref.7 Ref.9
Subcellular location	Nucleus. Cytoplasm. Note: Predominantly cytoplasmic but shuttles between the nucleus and the cytoplasm. Ref.5 Ref.7 Ref.9 Ref.10
Tissue specificity	Strongly expressed in lymph nodes and tonsils.
Post-translational modification	Ser-38 is the major site whereas Thr-27 is the minor site of phosphorylation. Phosphorylation regulates its class-switch recombination activity.
Involvement in disease	Immunodeficiency with hyper-IgM 2 (HIGM2) [MIM:605258]: A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.2
Sequence similarities	Belongs to the cytidine and deoxycytidylate deaminase family.

Ontologies

Keywords
Biological process	mRNA processing
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	Metal-binding Zinc
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Non-traceable author statement Ref.2. Source: UniProtKB DNA demethylation Inferred from direct assay Ref.8. Source: UniProtKB cellular response to lipopolysaccharide Inferred from electronic annotation. Source: Compara isotype switching Inferred from electronic annotation. Source: Compara mRNA processing Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of methylation-dependent chromatin silencing Inferred from direct assay Ref.8. Source: UniProtKB somatic diversification of immunoglobulins Inferred from direct assay Ref.7. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.5Ref.7. Source: UniProtKB nucleus Inferred from direct assay Ref.5. Source: UniProtKB
Molecular_function	cytidine deaminase activity Inferred from direct assay Ref.7. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GADD45A	P24522	5	EBI-3834328,EBI-448167
TDG	Q13569	5	EBI-3834328,EBI-348333

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 198	198	Activation-induced cytidine deaminase		PRO_0000171687
Regions
	Region	1 – 30	30	Nuclear localization signal
	Region	39 – 42	4	Important for interaction with CTNNBL1
	Region	183 – 198	16	Nuclear export signal
Sites
	Active site	58	1	Proton donor By similarity
	Metal binding	56	1	Zinc; catalytic By similarity
	Metal binding	87	1	Zinc; catalytic By similarity
	Metal binding	90	1	Zinc; catalytic By similarity
Amino acid modifications
	Modified residue	27	1	Phosphothreonine; by PKA Ref.6
	Modified residue	38	1	Phosphoserine; by PKA Ref.6 Ref.7
Natural variations
	Natural variant	24	1	R → W in HIGM2; Completely abolishes nuclear import and interaction with CTNNBL1, diminishes interaction with KPNA1 and abolishes immunoglobulin class switching. Ref.2 Ref.9		VAR_013774
	Natural variant	25	1	R → C. Ref.11		VAR_014091
	Natural variant	80	1	W → R in HIGM2. Ref.2		VAR_013775
	Natural variant	106	1	L → P in HIGM2. Ref.2		VAR_013776
	Natural variant	139	1	M → V in HIGM2. Ref.2		VAR_013777
	Natural variant	151	1	F → S in HIGM2. Ref.2		VAR_013778
Experimental info
	Mutagenesis	10	1	K → A: Little effect on nuclear import; when associated with A-193. No effect on CTNNBL1 binding. Ref.9
	Mutagenesis	18	1	V → S: Greatly impaired nuclear import; when associated with V-19 and A-193. Reduced interaction with both CTNNBL1 and KPNA1, and abolishes immunoglobulin class switching; when associated with V-19. Ref.9
	Mutagenesis	19	1	R → V: Greatly impaired nuclear import; when associated with S-18 and A-193. Reduced interaction with both CTNNBL1 and KPNA1, and abolishes immunoglobulin class switching; when associated with S-18. Ref.9
	Mutagenesis	20	1	W → K: Impaired nuclear import; when associated with A-193. No effect on CTNNBL1 binding. Ref.9
	Mutagenesis	27	1	T → A: Loss of phosphorylation. No effect on cytidine deaminase activity. Impaired class-switch recombination activity. Ref.6 Ref.10
	Mutagenesis	27	1	T → E: Phosphomimetic mutant which shows loss of cytidine deaminase activity and impaired class-switch recombination activity. Ref.6 Ref.10
	Mutagenesis	38	1	S → A: Loss of phosphorylation. Impaired class-switch recombination activity. No effect on interaction with CTNNBL1. Ref.6 Ref.7
	Mutagenesis	38	1	S → D: No effect on interaction with CTNNBL1. Ref.6 Ref.7
	Mutagenesis	39 – 42	4	ATSF → GGQV: Greatly reduced interaction with CTNNBL1 but no effect on subcellular location, enzyme activity, ability to oligomerize nor on phosphorylation at Ser-38. Diminished antibody diversification. Ref.7
	Mutagenesis	50	1	R → G: Some reduced nuclear import; when associated with A-193. Ref.9
	Mutagenesis	112	1	R → D: Greatly reduced nuclear import; when associated with A-193. Ref.9
	Mutagenesis	193	1	F → A: Completely abolishes nuclear import; when associated with W-24 or D-112. Little affect on nuclear import; when associated with A-10. Greatly impaired nuclear import; when associated with K-20 or G-50. Almost completely abolishes nuclear import; when associated with S-18 and V-19. Ref.9

Sequences

	Sequence		Length	Mass (Da)
	Q9GZX7 [UniParc]. Last modified March 1, 2001. Version 1. Checksum: 3C27BB143DB184A9	FASTA	198	23,954
	10 20 30 40 50 60 MDSLLMNRRK FLYQFKNVRW AKGRRETYLC YVVKRRDSAT SFSLDFGYLR NKNGCHVELL 70 80 90 100 110 120 FLRYISDWDL DPGRCYRVTW FTSWSPCYDC ARHVADFLRG NPNLSLRIFT ARLYFCEDRK 130 140 150 160 170 180 AEPEGLRRLH RAGVQIAIMT FKDYFYCWNT FVENHERTFK AWEGLHENSV RLSRQLRRIL 190 LPLYEVDDLR DAFRTLGL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation, tissue distribution, and chromosomal localization of the human activation-induced cytidine deaminase (hAID) gene." Muto T., Muramatsu M., Taniwaki M., Kinoshita K., Honjo T. Genomics 68:85-88(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)." Revy P., Muto T., Levy Y., Geissmann F., Plebani A., Sanal O., Catalan N., Forveille M., Dufourcq-Lagelouse R., Gennery A., Tezcan I., Ersoy F., Kayserili H., Ugazio A.G., Brousse N., Muramatsu M., Notarangelo L.D., Kinoshita K. , Honjo T., Fischer A., Durandy A. Cell 102:565-575(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANTS HIGM2 TRP-24; ARG-80; PRO-106; VAL-139 AND SER-151.
[3]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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: B-cell.
[5]	"Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1." Ito S., Nagaoka H., Shinkura R., Begum N., Muramatsu M., Nakata M., Honjo T. Proc. Natl. Acad. Sci. U.S.A. 101:1975-1980(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[6]	"PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells." Pasqualucci L., Kitaura Y., Gu H., Dalla-Favera R. Proc. Natl. Acad. Sci. U.S.A. 103:395-400(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-27 AND SER-38, INTERACTION WITH PRKACA AND PRKAR1A, MUTAGENESIS OF THR-27 AND SER-38.
[7]	"Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1." Conticello S.G., Ganesh K., Xue K., Lu M., Rada C., Neuberger M.S. Mol. Cell 31:474-484(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CTNNBL1, FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-38, MASS SPECTROMETRY, MUTAGENESIS OF 39-ALA--PHE-42 AND SER-38.
[8]	"Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain." Guo J.U., Su Y., Zhong C., Ming G.L., Song H. Cell 145:423-434(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN DNA DEMETHYLATION.
[9]	"CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31." Ganesh K., Adam S., Taylor B., Simpson P., Rada C., Neuberger M. J. Biol. Chem. 286:17091-17102(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CTNNBL1, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-10; VAL-18; ARG-19; TRP-20; ARG-50; ARG-112 AND PHE-193, CHARACTERIZATION OF VARIANT TRP-24.
[10]	"Phosphorylation directly regulates the intrinsic DNA cytidine deaminase activity of activation-induced deaminase and APOBEC3G protein." Demorest Z.L., Li M., Harris R.S. J. Biol. Chem. 286:26568-26575(2011) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF THR-27.
[11]	"Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels." Noguchi E., Shibasaki M., Inudou M., Kamioka M., Yokouchi Y., Yamakawa-Kobayashi K., Hamaguchi H., Matsui A., Arinami T. J. Allergy Clin. Immunol. 108:382-386(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CYS-25.
+	Additional computationally mapped references.

Web resources

AICDAbase

AICDA mutation db

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB040431 mRNA. Translation: BAB12721.1. AB040430 Genomic DNA. Translation: BAB12720.1. BT007402 mRNA. Translation: AAP36066.1. BC006296 mRNA. Translation: AAH06296.1.
IPI	IPI00010186.
RefSeq	NP_065712.1. NM_020661.2.
UniGene	Hs.149342.
3D structure databases
ProteinModelPortal	Q9GZX7.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-48519N.
IntAct	Q9GZX7. 10 interactions.
MINT	MINT-4717382.
STRING	9606.ENSP00000229335.
PTM databases
PhosphoSite	Q9GZX7.
Polymorphism databases
DMDM	23813666.
Proteomic databases
PaxDb	Q9GZX7.
PRIDE	Q9GZX7.
Protocols and materials databases
DNASU	57379.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000229335; ENSP00000229335; ENSG00000111732.
GeneID	57379.
KEGG	hsa:57379.
UCSC	uc001qur.2. human.
Organism-specific databases
CTD	57379.
GeneCards	GC12M008754.
HGNC	HGNC:13203. AICDA.
MIM	605257. gene. 605258. phenotype.
neXtProt	NX_Q9GZX7.
Orphanet	101089. Hyper-IgM syndrome type 2.
PharmGKB	PA24644.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG39659.
HOGENOM	HOG000033754.
HOVERGEN	HBG050434.
InParanoid	Q9GZX7.
KO	K10989.
OMA	IMTFKDY.
OrthoDB	EOG4GQQ5W.
Enzyme and pathway databases
Pathway_Interaction_DB	il4_2pathway. IL4-mediated signaling events.
Gene expression databases
ArrayExpress	Q9GZX7.
Bgee	Q9GZX7.
CleanEx	HS_AICDA.
Genevestigator	Q9GZX7.
GermOnline	ENSG00000111732. Homo sapiens.
Family and domain databases
InterPro	IPR016192. APOBEC/CMP_deaminase_Zn-bd. IPR013158. APOBEC_N. IPR016193. Cytidine_deaminase-like. [Graphical view]
Pfam	PF08210. APOBEC_N. 1 hit. [Graphical view]
SUPFAM	SSF53927. Cytidine_deaminase-like. 1 hit.
PROSITE	PS00903. CYT_DCMP_DEAMINASES. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	57379.
NextBio	63478.
SOURCE	Search...

Entry information

Entry name

AICDA_HUMAN

Accession

Primary (citable) accession number: Q9GZX7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 10, 2002
Last sequence update:	March 1, 2001
Last modified:	May 29, 2013
This is version 111 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.