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Protein

Homeobox protein SIX1

Gene

SIX1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter. Regulates the expression of numerous genes, including MYC, CCND1 and EZR. Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1.By similarity4 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi124 – 18360HomeoboxPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • chromatin binding Source: Ensembl
  • DNA binding Source: UniProtKB
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: NTNU_SB
  • sequence-specific DNA binding Source: UniProtKB
  • sequence-specific DNA binding transcription factor activity Source: UniProtKB
  • transcription regulatory region DNA binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator, Developmental protein, Repressor

Keywords - Biological processi

Apoptosis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

SignaLinkiQ15475.

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX1
Alternative name(s):
Sine oculis homeobox homolog 1
Gene namesi
Name:SIX1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:10887. SIX1.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB-SubCell
  • nucleolus Source: HPA
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • transcription factor complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Deafness, autosomal dominant, 23 (DFNA23)1 Publication

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA form of non-syndromic deafness characterized by prelingual, bilateral, symmetric hearing loss with a conductive component present in some but not all patients.

See also OMIM:605192
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti133 – 1331Missing in DFNA23; in addition to deafness the patient had renal anomalies suggesting a branchiootorenal syndrome; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031026
Branchiootic syndrome 3 (BOS3)4 Publications

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA syndrome characterized by usually bilateral branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, and structural defects of the outer, middle or inner ear. Otic defects include malformed and hypoplastic pinnae, a narrowed external ear canal, bulbous internal auditory canal, stapes fixation, malformed and hypoplastic cochlea. Branchial and otic anomalies overlap with those seen in individuals with the branchiootorenal syndrome. However renal anomalies are absent in branchiootic syndrome patients.

See also OMIM:608389
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti17 – 171V → E in BOS3; crucial for interaction with EYA1 and EYA2 and transcription factor activity. 3 Publications
VAR_064948
Natural varianti73 – 731H → P in BOS3. 1 Publication
VAR_064949
Natural varianti106 – 1061V → G in BOS3; crucial for protein stability, DNA binding and transcription factor activity. 2 Publications
VAR_064950
Natural varianti110 – 1101R → Q in BOS3. 1 Publication
VAR_064951
Natural varianti110 – 1101R → W in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031024
Natural varianti112 – 1121R → C in BOS3; crucial for DNA binding and transcription factor activity. 2 Publications
VAR_064952
Natural varianti122 – 1221W → R in BOS3. 1 Publication
VAR_064953
Natural varianti129 – 1291Y → C in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031025

Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable.

Keywords - Diseasei

Deafness, Disease mutation, Non-syndromic deafness

Organism-specific databases

MIMi605192. phenotype.
608389. phenotype.
Orphaneti90635. Autosomal dominant non-syndromic sensorineural deafness type DFNA.
107. BOR syndrome.
52429. Branchio-otic syndrome.
PharmGKBiPA35787.

Polymorphism and mutation databases

BioMutaiSIX1.
DMDMi2495290.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 284284Homeobox protein SIX1PRO_0000049295Add
BLAST

Post-translational modificationi

Phosphorylated during interphase; becomes hyperphosphorylated during mitosis. Hyperphosphorylation impairs binding to promoter elements.1 Publication
Ubiquitinated by the anaphase promoting complex (APC), leading to its proteasomal degradation.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ15475.
PaxDbiQ15475.
PRIDEiQ15475.

PTM databases

PhosphoSiteiQ15475.

Expressioni

Tissue specificityi

Specifically expressed in skeletal muscle.

Gene expression databases

BgeeiQ15475.
CleanExiHS_SIX1.
ExpressionAtlasiQ15475. baseline and differential.
GenevisibleiQ15475. HS.

Organism-specific databases

HPAiCAB058690.
HPA001893.

Interactioni

Subunit structurei

Interacts with DACH1 and EYA3 (By similarity). Interacts with EYA1 and EYA2. Interacts with CDC20.By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AESQ081173EBI-743675,EBI-717810
MDFIQ997502EBI-743675,EBI-724076

Protein-protein interaction databases

BioGridi112386. 13 interactions.
DIPiDIP-34448N.
IntActiQ15475. 5 interactions.
MINTiMINT-140054.
STRINGi9606.ENSP00000247182.

Structurei

Secondary structure

1
284
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi11 – 2313Combined sources
Helixi27 – 3610Combined sources
Helixi47 – 6014Combined sources
Helixi63 – 7210Combined sources
Helixi77 – 793Combined sources
Helixi80 – 9920Combined sources
Helixi105 – 11410Combined sources
Helixi135 – 14511Combined sources
Helixi151 – 16111Combined sources
Helixi165 – 18420Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4EGCX-ray1.99A1-189[»]
ProteinModelPortaliQ15475.
SMRiQ15475. Positions 1-185.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated
Contains 1 homeobox DNA-binding domain.PROSITE-ProRule annotation

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiNOG289502.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiQ15475.
KOiK15614.
OMAiFAQPREG.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ15475.
TreeFamiTF315545.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q15475-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSMLPSFGFT QEQVACVCEV LQQGGNLERL GRFLWSLPAC DHLHKNESVL
60 70 80 90 100
KAKAVVAFHR GNFRELYKIL ESHQFSPHNH PKLQQLWLKA HYVEAEKLRG
110 120 130 140 150
RPLGAVGKYR VRRKFPLPRT IWDGEETSYC FKEKSRGVLR EWYAHNPYPS
160 170 180 190 200
PREKRELAEA TGLTTTQVSN WFKNRRQRDR AAEAKERENT ENNNSSSNKQ
210 220 230 240 250
NQLSPLEGGK PLMSSSEEEF SPPQSPDQNS VLLLQGNMGH ARSSNYSLPG
260 270 280
LTASQPSHGL QTHQHQLQDS LLGPLTSSLV DLGS
Length:284
Mass (Da):32,210
Last modified:November 1, 1996 - v1
Checksum:iA4195376CFB9E3EA
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti17 – 171V → E in BOS3; crucial for interaction with EYA1 and EYA2 and transcription factor activity. 3 Publications
VAR_064948
Natural varianti73 – 731H → P in BOS3. 1 Publication
VAR_064949
Natural varianti99 – 991R → C.2 Publications
Corresponds to variant rs17850414 [ dbSNP | Ensembl ].
VAR_067446
Natural varianti106 – 1061V → G in BOS3; crucial for protein stability, DNA binding and transcription factor activity. 2 Publications
VAR_064950
Natural varianti110 – 1101R → Q in BOS3. 1 Publication
VAR_064951
Natural varianti110 – 1101R → W in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031024
Natural varianti112 – 1121R → C in BOS3; crucial for DNA binding and transcription factor activity. 2 Publications
VAR_064952
Natural varianti122 – 1221W → R in BOS3. 1 Publication
VAR_064953
Natural varianti129 – 1291Y → C in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031025
Natural varianti133 – 1331Missing in DFNA23; in addition to deafness the patient had renal anomalies suggesting a branchiootorenal syndrome; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 Publications
VAR_031026
Natural varianti249 – 2491P → L in BOR; uncertain pathological significance. 1 Publication
VAR_064954

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X91868 mRNA. Translation: CAA62974.1.
AF323497 Genomic DNA. Translation: AAK06772.1.
BT007083 mRNA. Translation: AAP35746.1.
BC008874 mRNA. Translation: AAH08874.1.
CCDSiCCDS9748.1.
RefSeqiNP_005973.1. NM_005982.3.
UniGeneiHs.633506.

Genome annotation databases

EnsembliENST00000247182; ENSP00000247182; ENSG00000126778.
GeneIDi6495.
KEGGihsa:6495.
UCSCiuc001xfb.4. human.

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X91868 mRNA. Translation: CAA62974.1.
AF323497 Genomic DNA. Translation: AAK06772.1.
BT007083 mRNA. Translation: AAP35746.1.
BC008874 mRNA. Translation: AAH08874.1.
CCDSiCCDS9748.1.
RefSeqiNP_005973.1. NM_005982.3.
UniGeneiHs.633506.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4EGCX-ray1.99A1-189[»]
ProteinModelPortaliQ15475.
SMRiQ15475. Positions 1-185.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112386. 13 interactions.
DIPiDIP-34448N.
IntActiQ15475. 5 interactions.
MINTiMINT-140054.
STRINGi9606.ENSP00000247182.

PTM databases

PhosphoSiteiQ15475.

Polymorphism and mutation databases

BioMutaiSIX1.
DMDMi2495290.

Proteomic databases

MaxQBiQ15475.
PaxDbiQ15475.
PRIDEiQ15475.

Protocols and materials databases

DNASUi6495.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000247182; ENSP00000247182; ENSG00000126778.
GeneIDi6495.
KEGGihsa:6495.
UCSCiuc001xfb.4. human.

Organism-specific databases

CTDi6495.
GeneCardsiGC14M061113.
GeneReviewsiSIX1.
HGNCiHGNC:10887. SIX1.
HPAiCAB058690.
HPA001893.
MIMi601205. gene.
605192. phenotype.
608389. phenotype.
neXtProtiNX_Q15475.
Orphaneti90635. Autosomal dominant non-syndromic sensorineural deafness type DFNA.
107. BOR syndrome.
52429. Branchio-otic syndrome.
PharmGKBiPA35787.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG289502.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiQ15475.
KOiK15614.
OMAiFAQPREG.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ15475.
TreeFamiTF315545.

Enzyme and pathway databases

SignaLinkiQ15475.

Miscellaneous databases

ChiTaRSiSIX1. human.
GeneWikiiSIX1.
GenomeRNAii6495.
NextBioi25247.
PROiQ15475.
SOURCEiSearch...

Gene expression databases

BgeeiQ15475.
CleanExiHS_SIX1.
ExpressionAtlasiQ15475. baseline and differential.
GenevisibleiQ15475. HS.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning of the human SIX1 gene and its assignment to chromosome 14."
    Boucher C.A., Carey N., Edwards Y.H., Siciliano M.J., Johnson K.J.
    Genomics 33:140-142(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Muscle.
  2. "Partial genomic sequence of human SIX1."
    Gallardo M.E., Rodriguez de Cordoba S.
    Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  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], VARIANT CYS-99.
  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], VARIANT CYS-99.
    Tissue: Muscle.
  5. "Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein."
    Ford H.L., Landesman-Bollag E., Dacwag C.S., Stukenberg P.T., Pardee A.B., Seldin D.C.
    J. Biol. Chem. 275:22245-22254(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION.
  6. Cited for: FUNCTION.
  7. "Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1)."
    Christensen K.L., Brennan J.D., Aldridge C.S., Ford H.L.
    Oncogene 26:3406-3414(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: UBIQUITINATION, INTERACTION WITH CDC20, SUBCELLULAR LOCATION.
  8. "Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome."
    Patrick A.N., Cabrera J.H., Smith A.L., Chen X.S., Ford H.L., Zhao R.
    Nat. Struct. Mol. Biol. 20:447-453(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) OF 1-189 IN COMPLEX WITH EYA2, FUNCTION, SUBUNIT, DNA-BINDING, CHARACTERIZATION OF VARIANT BOS3 GLU-17, CHARACTERIZATION OF VARIANT DFNA23 GLU-133 DEL.
  9. Cited for: VARIANTS BOS3 TRP-110 AND CYS-129, VARIANT DFNA23 GLU-133 DEL, CHARACTERIZATION OF VARIANTS BOS3 TRP-110 AND CYS-129, CHARACTERIZATION OF VARIANT DFNA23 GLU-133 DEL, FUNCTION, INTERACTION WITH EYA1.
  10. "Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses."
    Sanggaard K.M., Rendtorff N.D., Kjaer K.W., Eiberg H., Johnsen T., Gimsing S., Dyrmose J., Nielsen K.O., Lage K., Tranebjaerg L.
    Eur. J. Hum. Genet. 15:1121-1131(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT BOS3 ARG-122.
  11. "SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR."
    Kochhar A., Orten D.J., Sorensen J.L., Fischer S.M., Cremers C.W., Kimberling W.J., Smith R.J.
    Hum. Mutat. 29:565-565(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS BOS3 GLU-17; PRO-73; GLY-106; GLN-110; TRP-110; CYS-112 AND CYS-129.
  12. "Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations."
    Patrick A.N., Schiemann B.J., Yang K., Zhao R., Ford H.L.
    J. Biol. Chem. 284:20781-20790(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION OF VARIANTS BOS3 GLU-17; GLY-106; TRP-110 AND CYS-112, CHARACTERIZATION OF VARIANT DFNA23 GLU-133 DEL, FUNCTION, DNA-BINDING, SUBCELLULAR LOCATION, INTERACTION WITH EYA1 AND EYA2.
  13. "Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations."
    Krug P., Moriniere V., Marlin S., Koubi V., Gabriel H.D., Colin E., Bonneau D., Salomon R., Antignac C., Heidet L.
    Hum. Mutat. 32:183-190(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT BOS3 CYS-129, VARIANT BOR LEU-249.

Entry informationi

Entry nameiSIX1_HUMAN
AccessioniPrimary (citable) accession number: Q15475
Secondary accession number(s): Q53Y16, Q96H64
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: June 24, 2015
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.