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Protein

Homeobox protein SIX1

Gene

SIX1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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)DescriptionActionsGraphical viewLength
DNA bindingi124 – 183HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, Developmental protein, DNA-binding, Repressor
Biological processApoptosis, Transcription, Transcription regulation

Enzyme and pathway databases

SignaLinkiQ15475
SIGNORiQ15475

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
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

EuPathDBiHostDB:ENSG00000126778.8
HGNCiHGNC:10887 SIX1
MIMi601205 gene
neXtProtiNX_Q15475

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Deafness, autosomal dominant, 23 (DFNA23)3 Publications
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)DescriptionActionsGraphical viewLength
Natural variantiVAR_031026133Missing 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 Publications1
Branchiootic syndrome 3 (BOS3)6 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)DescriptionActionsGraphical viewLength
Natural variantiVAR_06494817V → E in BOS3; crucial for interaction with EYA1 and EYA2 and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs397515562EnsemblClinVar.1
Natural variantiVAR_06494973H → P in BOS3. 1 Publication1
Natural variantiVAR_064950106V → G in BOS3; crucial for protein stability, DNA binding and transcription factor activity. 2 PublicationsCorresponds to variant dbSNP:rs397515560EnsemblClinVar.1
Natural variantiVAR_064951110R → Q in BOS3. 1 PublicationCorresponds to variant dbSNP:rs1064794308Ensembl.1
Natural variantiVAR_031024110R → W in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs80356459EnsemblClinVar.1
Natural variantiVAR_064952112R → C in BOS3; crucial for DNA binding and transcription factor activity. 2 PublicationsCorresponds to variant dbSNP:rs397515561EnsemblClinVar.1
Natural variantiVAR_064953122W → R in BOS3. 1 PublicationCorresponds to variant dbSNP:rs121909770EnsemblClinVar.1
Natural variantiVAR_031025129Y → C in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs104894478EnsemblClinVar.1
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.2 Publications

Keywords - Diseasei

Deafness, Disease mutation, Non-syndromic deafness

Organism-specific databases

DisGeNETi6495
GeneReviewsiSIX1
MalaCardsiSIX1
MIMi605192 phenotype
608389 phenotype
OpenTargetsiENSG00000126778
Orphaneti90635 Autosomal dominant non-syndromic sensorineural deafness type DFNA
107 BOR syndrome
52429 Branchiootic syndrome
PharmGKBiPA35787

Polymorphism and mutation databases

BioMutaiSIX1
DMDMi2495290

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000492951 – 284Homeobox protein SIX1Add BLAST284

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
PeptideAtlasiQ15475
PRIDEiQ15475
ProteomicsDBi60606

PTM databases

iPTMnetiQ15475
PhosphoSitePlusiQ15475

Expressioni

Tissue specificityi

Specifically expressed in skeletal muscle.

Gene expression databases

BgeeiENSG00000126778 Expressed in 130 organ(s), highest expression level in vastus lateralis
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. Interacts with TBX18 (PubMed:26235987).By similarity5 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi112386, 16 interactors
DIPiDIP-34448N
IntActiQ15475, 13 interactors
MINTiQ15475
STRINGi9606.ENSP00000247182

Structurei

Secondary structure

1284
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ15475
SMRiQ15475
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiKOG0775 Eukaryota
ENOG410XRPB LUCA
GeneTreeiENSGT00540000070251
HOGENOMiHOG000261680
HOVERGENiHBG003609
InParanoidiQ15475
KOiK15614
OMAiSAYPMSG
OrthoDBiEOG091G083I
PhylomeDBiQ15475
TreeFamiTF315545

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR017970 Homeobox_CS
IPR001356 Homeobox_dom
IPR031278 SIX1
IPR031701 SIX1_SD
PANTHERiPTHR10390:SF13 PTHR10390:SF13, 1 hit
PfamiView protein in Pfam
PF00046 Homeobox, 1 hit
PF16878 SIX1_SD, 1 hit
SMARTiView protein in SMART
SM00389 HOX, 1 hit
SUPFAMiSSF46689 SSF46689, 1 hit
PROSITEiView protein in PROSITE
PS00027 HOMEOBOX_1, 1 hit
PS50071 HOMEOBOX_2, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0YK85H0YK85_HUMAN
Homeobox protein SIX1
SIX1
111Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06494817V → E in BOS3; crucial for interaction with EYA1 and EYA2 and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs397515562EnsemblClinVar.1
Natural variantiVAR_06494973H → P in BOS3. 1 Publication1
Natural variantiVAR_06744699R → C2 PublicationsCorresponds to variant dbSNP:rs17850414Ensembl.1
Natural variantiVAR_064950106V → G in BOS3; crucial for protein stability, DNA binding and transcription factor activity. 2 PublicationsCorresponds to variant dbSNP:rs397515560EnsemblClinVar.1
Natural variantiVAR_064951110R → Q in BOS3. 1 PublicationCorresponds to variant dbSNP:rs1064794308Ensembl.1
Natural variantiVAR_031024110R → W in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs80356459EnsemblClinVar.1
Natural variantiVAR_064952112R → C in BOS3; crucial for DNA binding and transcription factor activity. 2 PublicationsCorresponds to variant dbSNP:rs397515561EnsemblClinVar.1
Natural variantiVAR_064953122W → R in BOS3. 1 PublicationCorresponds to variant dbSNP:rs121909770EnsemblClinVar.1
Natural variantiVAR_031025129Y → C in BOS3; crucial for interaction with EYA1, DNA binding and transcription factor activity. 3 PublicationsCorresponds to variant dbSNP:rs104894478EnsemblClinVar.1
Natural variantiVAR_031026133Missing 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 Publications1
Natural variantiVAR_064954249P → L in BOR; uncertain pathological significance. 1 PublicationCorresponds to variant dbSNP:rs368974927Ensembl.1

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
ENST00000645694; ENSP00000494686; ENSG00000126778
GeneIDi6495
KEGGihsa:6495
UCSCiuc001xfb.5 human

Similar proteinsi

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
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4EGCX-ray1.99A1-189[»]
ProteinModelPortaliQ15475
SMRiQ15475
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112386, 16 interactors
DIPiDIP-34448N
IntActiQ15475, 13 interactors
MINTiQ15475
STRINGi9606.ENSP00000247182

PTM databases

iPTMnetiQ15475
PhosphoSitePlusiQ15475

Polymorphism and mutation databases

BioMutaiSIX1
DMDMi2495290

Proteomic databases

MaxQBiQ15475
PaxDbiQ15475
PeptideAtlasiQ15475
PRIDEiQ15475
ProteomicsDBi60606

Protocols and materials databases

DNASUi6495
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000247182; ENSP00000247182; ENSG00000126778
ENST00000645694; ENSP00000494686; ENSG00000126778
GeneIDi6495
KEGGihsa:6495
UCSCiuc001xfb.5 human

Organism-specific databases

CTDi6495
DisGeNETi6495
EuPathDBiHostDB:ENSG00000126778.8
GeneCardsiSIX1
GeneReviewsiSIX1
HGNCiHGNC:10887 SIX1
HPAiCAB058690
HPA001893
MalaCardsiSIX1
MIMi601205 gene
605192 phenotype
608389 phenotype
neXtProtiNX_Q15475
OpenTargetsiENSG00000126778
Orphaneti90635 Autosomal dominant non-syndromic sensorineural deafness type DFNA
107 BOR syndrome
52429 Branchiootic syndrome
PharmGKBiPA35787
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0775 Eukaryota
ENOG410XRPB LUCA
GeneTreeiENSGT00540000070251
HOGENOMiHOG000261680
HOVERGENiHBG003609
InParanoidiQ15475
KOiK15614
OMAiSAYPMSG
OrthoDBiEOG091G083I
PhylomeDBiQ15475
TreeFamiTF315545

Enzyme and pathway databases

SignaLinkiQ15475
SIGNORiQ15475

Miscellaneous databases

ChiTaRSiSIX1 human
GeneWikiiSIX1
GenomeRNAii6495
PROiPR:Q15475
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000126778 Expressed in 130 organ(s), highest expression level in vastus lateralis
CleanExiHS_SIX1
ExpressionAtlasiQ15475 baseline and differential
GenevisibleiQ15475 HS

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR017970 Homeobox_CS
IPR001356 Homeobox_dom
IPR031278 SIX1
IPR031701 SIX1_SD
PANTHERiPTHR10390:SF13 PTHR10390:SF13, 1 hit
PfamiView protein in Pfam
PF00046 Homeobox, 1 hit
PF16878 SIX1_SD, 1 hit
SMARTiView protein in SMART
SM00389 HOX, 1 hit
SUPFAMiSSF46689 SSF46689, 1 hit
PROSITEiView protein in PROSITE
PS00027 HOMEOBOX_1, 1 hit
PS50071 HOMEOBOX_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSIX1_HUMAN
AccessioniPrimary (citable) accession number: Q15475
Secondary accession number(s): Q53Y16, Q96H64
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: November 7, 2018
This is version 169 of the entry and version 1 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  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. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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