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O95409 (ZIC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 133. 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:
Zinc finger protein ZIC 2
Alternative name(s):
Zinc finger protein of the cerebellum 2
Gene names
Name:ZIC2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length532 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Acts as a transcriptional activator or repressor. Plays important roles in the early stage of organogenesis of the CNS. Activates the transcription of the serotonin transporter SERT in uncrossed ipsilateral retinal ganglion cells (iRGCs) to refine eye-specific projections in primary visual targets. Its transcriptional activity is repressed by MDFIC. Involved in the formation of the ipsilateral retinal projection at the optic chiasm midline. Drives the expression of EPHB1 on ipsilaterally projecting growth cones. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3'. Associates to the basal SERT promoter region from ventrotemporal retinal segments of retinal embryos.

Subunit structure

Interacts with RNF180. Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity. Interacts with DHX9 By similarity.

Subcellular location

Nucleus. Cytoplasm By similarity. Note: Localizes in the cytoplasm in presence of MDFIC overexpression. Both phosphorylated and unphosphorylated forms are localized in the nucleus By similarity.

Domain

The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation By similarity.

Post-translational modification

Phosphorylated.

Ubiquitinated by RNF180, leading to its degradation.

Polymorphism

The poly-His region between amino acids 231-239 of ZIC2 is polymorphic and the number of His can vary from 8 to 12.

Involvement in disease

Holoprosencephaly 5 (HPE5) [MIM:609637]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.4 Ref.5 Ref.6 Ref.7

Sequence similarities

Belongs to the GLI C2H2-type zinc-finger protein family.

Contains 5 C2H2-type zinc fingers.

Ontologies

Keywords
   Biological processDifferentiation
Neurogenesis
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
Holoprosencephaly
   DomainRepeat
Zinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionActivator
Developmental protein
Repressor
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbrain development

Traceable author statement Ref.1. Source: ProtInc

developmental pigmentation

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

neural tube closure

Inferred from electronic annotation. Source: Ensembl

positive regulation of sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

retinal ganglion cell axon guidance

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

visual perception

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

chromatin DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 532532Zinc finger protein ZIC 2
PRO_0000047247

Regions

Zinc finger256 – 29136C2H2-type 1; atypical
Zinc finger300 – 32728C2H2-type 2; atypical
Zinc finger333 – 35725C2H2-type 3
Zinc finger363 – 38725C2H2-type 4
Zinc finger393 – 41523C2H2-type 5
Region100 – 255156Necessary for interaction with MDFIC and transcriptional activation or repression By similarity
Compositional bias20 – 234Poly-His
Compositional bias25 – 339Poly-Ala
Compositional bias89 – 979Poly-Ala
Compositional bias226 – 2305Poly-Ala
Compositional bias231 – 2399Poly-His
Compositional bias456 – 47015Poly-Ala
Compositional bias490 – 50819Poly-Gly

Amino acid modifications

Modified residue1911Phosphoserine By similarity
Modified residue1991Phosphoserine By similarity

Natural variations

Natural variant361Q → P in HPE5; 2-fold increase in luciferase activity. Ref.5 Ref.6
VAR_023793
Natural variant371D → N in HPE5. Ref.7
VAR_058592
Natural variant1281D → N in HPE5. Ref.7
VAR_058593
Natural variant1521D → F in HPE5; requires 2 nucleotide substitutions; 50% reduction of luciferase activity. Ref.4 Ref.5 Ref.6
VAR_023794
Natural variant2391H → HH. Ref.5
VAR_023795
Natural variant2391Missing. Ref.5
VAR_023796
Natural variant2721S → N in HPE5. Ref.7
VAR_058594
Natural variant2861H → L in HPE5. Ref.7
VAR_058595
Natural variant2861H → Q in HPE5. Ref.7
VAR_058596
Natural variant2861H → Y in HPE5. Ref.7
VAR_058597
Natural variant2911H → Y in HPE5. Ref.7
VAR_058598
Natural variant3041W → R in HPE5. Ref.7
VAR_058599
Natural variant3141F → C in HPE5. Ref.7
VAR_058600
Natural variant3251R → L in HPE5. Ref.7
VAR_058601
Natural variant3251R → S in HPE5. Ref.7
VAR_058602
Natural variant3271H → Y in HPE5. Ref.7
VAR_058603
Natural variant3351C → F in HPE5. Ref.7
VAR_058604
Natural variant3731R → P in HPE5. Ref.7
VAR_058605
Natural variant4021Y → N in HPE5. Ref.7
VAR_058606
Natural variant4031T → K in HPE5. Ref.7
VAR_058607
Natural variant4041H → R in HPE5. Ref.7
VAR_058608
Natural variant4091R → W in HPE5. Ref.7
VAR_058609
Natural variant4151H → Q in HPE5. Ref.7
VAR_058610
Natural variant4701A → AAAAAAAAAAA in HPE5; near-complete loss of luciferase activity.
VAR_008856

Experimental info

Sequence conflict124 – 1285RGFGD → ARLPGT in AAC96325. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O95409 [UniParc].

Last modified April 16, 2002. Version 2.
Checksum: BA3E6455DAF97EAC

FASTA53255,006
        10         20         30         40         50         60 
MLLDAGPQFP AIGVGSFARH HHHSAAAAAA AAAEMQDREL SLAAAQNGFV DSAAAHMGAF 

        70         80         90        100        110        120 
KLNPGAHELS PGQSSAFTSQ GPGAYPGSAA AAAAAAALGP HAAHVGSYSG PPFNSTRDFL 

       130        140        150        160        170        180 
FRSRGFGDSA PGGGQHGLFG PGAGGLHHAH SDAQGHLLFP GLPEQHGPHG SQNVLNGQMR 

       190        200        210        220        230        240 
LGLPGEVFGR SEQYRQVASP RTDPYSAAQL HNQYGPMNMN MGMNMAAAAA HHHHHHHHHP 

       250        260        270        280        290        300 
GAFFRYMRQQ CIKQELICKW IDPEQLSNPK KSCNKTFSTM HELVTHVSVE HVGGPEQSNH 

       310        320        330        340        350        360 
VCFWEECPRE GKPFKAKYKL VNHIRVHTGE KPFPCPFPGC GKVFARSENL KIHKRTHTGE 

       370        380        390        400        410        420 
KPFQCEFEGC DRRFANSSDR KKHMHVHTSD KPYLCKMCDK SYTHPSSLRK HMKVHESSPQ 

       430        440        450        460        470        480 
GSESSPAASS GYESSTPPGL VSPSAEPQSS SNLSPAAAAA AAAAAAAAAA VSAVHRGGGS 

       490        500        510        520        530 
GSGGAGGGSG GGSGSGGGGG GAGGGGGGSS GGGSGTAGGH SGLSSNFNEW YV 

« Hide

References

« Hide 'large scale' references
[1]"Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired."
Brown S.A., Warburton D., Brown L.Y., Yu C.Y., Roeder E.R., Stengel-Rutkowski S., Hennekam R.C.M., Muenke M.
Nat. Genet. 20:180-183(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION OF VARIANT HPE5 POLY-ALA INS.
[2]"ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene."
Yang Y., Hwang C.K., Junn E., Lee G., Mouradian M.M.
J. Biol. Chem. 275:38863-38869(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[3]"The DNA sequence and analysis of human chromosome 13."
Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.
Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination."
Brown L.Y., Odent S., David V., Blayau M., Dubourg C., Apacik C., Delgado M.A., Hall B.D., Reynolds J.F., Sommer A., Wieczorek D., Brown S.A., Muenke M.
Hum. Mol. Genet. 10:791-796(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HPE5 POLY-ALA INS AND PHE-152, POLYMORPHISM OF POLY-HIS REGION.
[5]"Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations."
Dubourg C., Lazaro L., Pasquier L., Bendavid C., Blayau M., Le Duff F., Durou M.-R., Odent S., David V.
Hum. Mutat. 24:43-51(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HPE5 PRO-36 AND PHE-152, VARIANTS HIS-239 INS AND HIS-239 DEL.
[6]"In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation."
Brown L., Paraso M., Arkell R., Brown S.
Hum. Mol. Genet. 14:411-420(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS HPE5 PRO-36; PHE-152 AND POLY-ALA INS.
[7]"The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism."
Roessler E., Lacbawan F., Dubourg C., Paulussen A., Herbergs J., Hehr U., Bendavid C., Zhou N., Ouspenskaia M., Bale S., Odent S., David V., Muenke M.
Hum. Mutat. 30:E541-E554(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HPE5 ASN-37; ASN-128; ASN-272; LEU-286; GLN-286; TYR-286; TYR-291; ARG-304; CYS-314; SER-325; LEU-325; TYR-327; PHE-335; PRO-373; ASN-402; LYS-403; ARG-404; TRP-409 AND GLN-415.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF104902 mRNA. Translation: AAC96325.1.
AF193855 mRNA. Translation: AAG28409.1.
AL355338 Genomic DNA. Translation: CAH70367.1.
RefSeqNP_009060.2. NM_007129.3.
UniGeneHs.653700.

3D structure databases

ProteinModelPortalO95409.
SMRO95409. Positions 250-417.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid113378. 7 interactions.
IntActO95409. 1 interaction.
MINTMINT-2798893.
STRING9606.ENSP00000365514.

PTM databases

PhosphoSiteO95409.

Proteomic databases

PaxDbO95409.
PeptideAtlasO95409.
PRIDEO95409.

Protocols and materials databases

DNASU7546.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000376335; ENSP00000365514; ENSG00000043355.
GeneID7546.
KEGGhsa:7546.
UCSCuc001von.3. human.

Organism-specific databases

CTD7546.
GeneCardsGC13P100634.
HGNCHGNC:12873. ZIC2.
MIM603073. gene.
609637. phenotype.
neXtProtNX_O95409.
Orphanet93925. Alobar holoprosencephaly.
93924. Lobar holoprosencephaly.
280200. Microform holoprosencephaly.
93926. Midline interhemispheric variant of holoprosencephaly.
220386. Semilobar holoprosencephaly.
280195. Septopreoptic holoprosencephaly.
PharmGKBPA37462.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5048.
HOGENOMHOG000232057.
HOVERGENHBG007135.
InParanoidO95409.
KOK06235.
OMADSAHMGA.
OrthoDBEOG76472R.
PhylomeDBO95409.
TreeFamTF351425.

Enzyme and pathway databases

SignaLinkO95409.

Gene expression databases

BgeeO95409.
CleanExHS_ZIC2.
GenevestigatorO95409.

Family and domain databases

Gene3D3.30.160.60. 4 hits.
InterProIPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]
PfamPF00096. zf-C2H2. 1 hit.
[Graphical view]
SMARTSM00355. ZnF_C2H2. 5 hits.
[Graphical view]
PROSITEPS00028. ZINC_FINGER_C2H2_1. 3 hits.
PS50157. ZINC_FINGER_C2H2_2. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiZIC2.
GenomeRNAi7546.
NextBio29525.
PROO95409.
SOURCESearch...

Entry information

Entry nameZIC2_HUMAN
AccessionPrimary (citable) accession number: O95409
Secondary accession number(s): Q5VYA9, Q9H309
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: April 16, 2002
Last modified: April 16, 2014
This is version 133 of the entry and version 2 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 13

Human chromosome 13: entries, gene names and cross-references to MIM