O60481 (ZIC3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Zinc finger protein ZIC 3

Alternative name(s):
Zinc finger protein 203
Zinc finger protein of the cerebellum 3

Gene names

Name:	ZIC3
Synonyms:	ZNF203

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. Ref.6
Subunit structure	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 By similarity. Interacts with KPNA1 and KPNA6. Interacts (via C2H2-type domains 3, 4 and 5) with GLI3; the interaction enhances its transcriptional activity. Ref.5 Ref.6
Subcellular location	Nucleus. Cytoplasm By similarity. Note: Localizes in the cytoplasm in presence of MDFIC overexpression By similarity. Translocation to the nucleus requires KPNA1 or KPNA6.
Domain	The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation By similarity.
Involvement in disease	Defects in ZIC3 are the cause of visceral heterotaxy X-linked type 1 (HTX1) [MIM:306955]. A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. It results in an abnormal arrangement of visceral organs, and a wide variety of congenital defects. Clinical features of visceral heterotaxy X-linked type 1 include dextrocardia, corrected transposition of great arteries, ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, situs inversus viscerum, and asplenia and/or polysplenia. Ref.1 Ref.5 Ref.6 Ref.8 Ref.10 Defects in ZIC3 are a cause of VACTERL association X-linked with or without hydrocephalus (VACTERLX) [MIM:314390]. A syndrome characterized by vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb). Some patients may have hydrocephalus. Some cases of VACTERL-H are associated with increased chromosome breakage and rearrangement. Ref.11
Sequence similarities	Belongs to the GLI C2H2-type zinc-finger protein family. Contains 5 C2H2-type zinc fingers.

Ontologies

Keywords
Biological process	Differentiation Neurogenesis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism Triplet repeat expansion
Disease	Disease mutation Heterotaxy
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator Developmental protein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.6. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	protein binding Inferred from physical interaction Ref.6Ref.5. Source: UniProtKB sequence-specific DNA binding Inferred from direct assay Ref.6. Source: UniProtKB sequence-specific DNA binding transcription factor activity Inferred from direct assay Ref.6. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 467

467

Zinc finger protein ZIC 3

PRO_0000047250

Regions

Zinc finger

251 – 286

36

C2H2-type 1; atypical

Zinc finger

295 – 322

28

C2H2-type 2; atypical

Zinc finger

328 – 352

25

C2H2-type 3

Zinc finger

358 – 382

25

C2H2-type 4

Zinc finger

388 – 410

23

C2H2-type 5

Region

297 – 322

26

Nuclear localization signal

Region

330 – 352

23

Nuclear localization signal

Compositional bias

46 – 55

10

Poly-Ala

Compositional bias

87 – 97

11

Poly-His

Natural variations

Natural variant

46

1

A → AAA in VACTERLX. Ref.11

VAR_066626

Natural variant

217

1

P → A in a patient with atrial septal defect and pulmonic stenosis not associated with heterotaxy; lacks DNA-binding; does not inhibit transcriptional activation and interaction with GLI3. Ref.6 Ref.8 Ref.9

VAR_025632

Natural variant

253

1

C → S in HTX1; increases strongly its cytoplasmic localization; lacks DNA-binding; does not inhibit transcriptional activation and interaction with GLI3. Ref.5 Ref.6 Ref.8

VAR_025633

Natural variant

255

1

W → G in HTX1; decreases protein expression and transcriptional activity and increases its cytoplasmic localization. Ref.5 Ref.10

VAR_042416

Natural variant

286

1

H → R in HTX1; inreases weakly its cytoplasmic localization; lacks DNA-binding; does not inhibit transcriptional activation and interaction with GLI3. Ref.1 Ref.5 Ref.6

VAR_025634

Natural variant

323

1

T → M in HTX1; lacks DNA-binding; does not inhibit transcriptional activation and interaction with GLI3. Ref.1 Ref.6

VAR_007753

Natural variant

405

1

K → E in HTX1; lacks DNA-binding; does not inhibit transcriptional activation and interaction with GLI3. Ref.6 Ref.8

VAR_025635

Experimental info

Mutagenesis

268

1

C → S: Increases weakly its cytoplasmic localization. Ref.5

Mutagenesis

281

1

H → R: Increases its cytoplasmic localization. Ref.5

Mutagenesis

304

1

R → M: Increases its cytoplasmic localization. Ref.5

Mutagenesis

307

1

K → M: Increases its cytoplasmic localization. Ref.5

Mutagenesis

310

1

K → M: Increases its cytoplasmic localization. Ref.5

Mutagenesis

312

1

K → M: Increases its cytoplasmic localization. Ref.5

Mutagenesis

314

1

K → M: Does not increase its cytoplasmic localization. Ref.5

Mutagenesis

320

1

R → A: Increases its cytoplasmic localization. Does not interact with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-337; A-341; A-346; A-349 and A-350. Ref.5

Mutagenesis

326

1

K → M: Does not increase its cytoplasmic localization. Ref.5

Mutagenesis

337

1

K → A: Increases its cytoplasmic localization. Does not interact with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-320; A-341; A-346; A-349 and A-350. Ref.5

Mutagenesis

341

1

R → A: Increases its cytoplasmic localization. Does not interact with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-320; A-337; A-346; A-349 and A-350. Ref.5

Mutagenesis

346

1

K → A: Increases its cytoplasmic localization. Does not interact with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-320; A-337; A-341; A-349 and A-350. Ref.5

Mutagenesis

349

1

K → A: Increases its cytoplasmic localization. Does not interacts with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-320; A-337; A-341; A-346 and A-350. Ref.5

Mutagenesis

350

1

R → A: Increases its cytoplasmic localization. Does not interact with KPNA1 and KPNA6 and increases strongly its cytoplasmic localization; when associated with A-320; A-337; A-341; A-346 and A-349. Ref.5

Mutagenesis

356

1

K → A: Does not increase its cytoplasmic localization. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

467

Helix Strand Turn

Details...

Beta strand

261 – 264

4

Helix

275 – 284

10

Turn

285 – 287

3

Helix

312 – 323

12

Sequences

	Sequence		Length	Mass (Da)
	O60481 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 3150CF13C0679568	FASTA	467	50,569
	10 20 30 40 50 60 MTMLLDGGPQ FPGLGVGSFG APRHHEMPNR EPAGMGLNPF GDSTHAAAAA AAAAAFKLSP 70 80 90 100 110 120 AAAHDLSSGQ SSAFTPQGSG YANALGHHHH HHHHHHHTSQ VPSYGGAASA AFNSTREFLF 130 140 150 160 170 180 RQRSSGLSEA ASGGGQHGLF AGSASSLHAP AGIPEPPSYL LFPGLHEQGA GHPSPTGHVD 190 200 210 220 230 240 NNQVHLGLRG ELFGRADPYR PVASPRTDPY AAGAQFPNYS PMNMNMGVNV AAHHGPGAFF 250 260 270 280 290 300 RYMRQPIKQE LSCKWIDEAQ LSRPKKSCDR TFSTMHELVT HVTMEHVGGP EQNNHVCYWE 310 320 330 340 350 360 ECPREGKSFK AKYKLVNHIR VHTGEKPFPC PFPGCGKIFA RSENLKIHKR THTGEKPFKC 370 380 390 400 410 420 EFEGCDRRFA NSSDRKKHMH VHTSDKPYIC KVCDKSYTHP SSLRKHMKVH ESQGSDSSPA 430 440 450 460 ASSGYESSTP PAIASANSKD TTKTPSAVQT STSHNPGLPP NFNEWYV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"X-linked situs abnormalities result from mutations in ZIC3." Gebbia M., Ferrero G.B., Pilia G., Bassi M.T., Aylsworth A.S., Penman-Splitt M., Bird L.M., Bamforth J.S., Burn J., Schlessiner D., Nelson D.L., Casey B. Nat. Genet. 17:305-308(1997) [PubMed: 9354794] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS HTX1 ARG-286 AND MET-323.
[2]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed: 15772651] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Analysis of polyhistidine-containing proteins." Salichs E., de la Luna S. Submitted (FEB-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[5]	"Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain." Hatayama M., Tomizawa T., Sakai-Kato K., Bouvagnet P., Kose S., Imamoto N., Yokoyama S., Utsunomiya-Tate N., Mikoshiba K., Kigawa T., Aruga J. Hum. Mol. Genet. 17:3459-3473(2008) [PubMed: 18716025] [Abstract] Cited for: INTERACTION WITH KPNA1 AND KPNA6, CHARACTERIZATION OF VARIANTS HTX1 SER-253; GLY-255 AND ARG-286, MUTAGENESIS OF CYS-268; HIS-281; ARG-304; LYS-307; LYS-310; LYS-312; LYS-314; ARG-320; LYS-326; LYS-337; ARG-341; LYS-346; LYS-349; ARG-350 AND LYS-356.
[6]	"Characterization of the interactions of human ZIC3 mutants with GLI3." Zhu L., Zhou G., Poole S., Belmont J.W. Hum. Mutat. 29:99-105(2008) [PubMed: 17764085] [Abstract] Cited for: FUNCTION, INTERACTION WITH GLI3, DNA-BINDING, CHARACTERIZATION OF VARIANTS HTX1 ALA-217; SER-253; ARG-286; MET-323 AND GLU-405.
[7]	"Functional and structural basis of nuclear localization signal in ZIC3 zinc finger domain: a role of conserved tryptophan residue in the zinc finger domain." RIKEN structural genomics initiative (RSGI) Submitted (FEB-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 246-329 IN COMPLEX WITH ZINC IONS.
[8]	"Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects." Ware S.M., Peng J., Zhu L., Fernbach S., Colicos S., Casey B., Towbin J., Belmont J.W. Am. J. Hum. Genet. 74:93-105(2004) [PubMed: 14681828] [Abstract] Cited for: VARIANT ALA-217, VARIANTS HTX1 SER-253 AND GLU-405.
[9]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ALA-217.
[10]	"Elucidation of penetrance variability of a ZIC3 mutation in a family with complex heart defects and functional analysis of ZIC3 mutations in the first zinc finger domain." Chhin B., Hatayama M., Bozon D., Ogawa M., Schoen P., Tohmonda T., Sassolas F., Aruga J., Valard A.-G., Chen S.-C., Bouvagnet P. Hum. Mutat. 28:563-570(2007) [PubMed: 17295247] [Abstract] Cited for: VARIANT HTX1 GLY-255, CHARACTERIZATION OF VARIANT HTX1 GLY-255.
[11]	"Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?" Wessels M.W., Kuchinka B., Heydanus R., Smit B.J., Dooijes D., de Krijger R.R., Lequin M.H., de Jong E.M., Husen M., Willems P.J., Casey B. J. Med. Genet. 47:351-355(2010) [PubMed: 20452998] [Abstract] Cited for: VARIANT VACTERLX ALA-ALA-46 INS.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF028706 mRNA. Translation: AAC05594.1.
AL035443 Genomic DNA. Translation: CAB41648.1.
EU532020 mRNA. Translation: ACB30403.1.
BC113393 mRNA. Translation: AAI13394.1.
BC113395 mRNA. Translation: AAI13396.1.

IPI

IPI00029724.

RefSeq

NP_003404.1. NM_003413.3.

UniGene

Hs.111227.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EJ4	NMR	-	A	245-326	[»]
2RPC	NMR	-	A	245-386	[»]

ProteinModelPortal

O60481.

SMR

O60481. Positions 245-427.

ModBase

Search...

Protein-protein interaction databases

STRING

O60481.

Proteomic databases

PRIDE

O60481.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000287538; ENSP00000287538; ENSG00000156925.

GeneID

7547.

KEGG

hsa:7547.

UCSC

uc004fak.1. human.

Organism-specific databases

CTD

7547.

GeneCards

GC0XP136648.

HGNC

HGNC:12874. ZIC3.

MIM

300265. gene.
306955. phenotype.
314390. phenotype.

neXtProt

NX_O60481.

Orphanet

157769. Situs ambiguus.

PharmGKB

PA37463.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG09565.

GeneTree

ENSGT00600000084058.

HOGENOM

HBG506538.

HOVERGEN

HBG007135.

InParanoid

O60481.

OMA

RTDPYTA.

OrthoDB

EOG4FFD3K.

PhylomeDB

O60481.

Gene expression databases

ArrayExpress

O60481.

Bgee

O60481.

CleanEx

HS_ZIC3.

Genevestigator

O60481.

GermOnline

ENSG00000156925. Homo sapiens.

Family and domain databases

InterPro

IPR007087. Znf_C2H2.
IPR015880. Znf_C2H2-like.
IPR013087. Znf_C2H2/integrase_DNA-bd.
[Graphical view]

Gene3D

G3DSA:3.30.160.60. Znf_C2H2/integrase_DNA-bd. 4 hits.

KO

K09224.

Pfam

PF00096. zf-C2H2. 4 hits.
[Graphical view]

SMART

SM00355. ZnF_C2H2. 5 hits.
[Graphical view]

PROSITE

PS00028. ZINC_FINGER_C2H2_1. 3 hits.
PS50157. ZINC_FINGER_C2H2_2. 4 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

29529.

SOURCE

Search...

Entry information

Entry name

ZIC3_HUMAN

Accession

Primary (citable) accession number: O60481
Secondary accession number(s): B2CNW4, Q14DE5

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	August 1, 1998
Last modified:	January 25, 2012
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.