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Protein

Homeobox protein SIX4

Gene

SIX4

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

Functioni

Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present in the Trex site and a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer. Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein. Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1. Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6. Controls somitic differentiation in myocyte through MYOG transactivation. Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes. During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression. During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation. During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation. Promotes survival of sensory neurons during early trigeminal gangliogenesis. In the developing dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression. Forms gustatory papillae during development of the tongue. Also plays a role during embryonic cranial skeleton morphogenesis.By similarity

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi223 – 282HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, DNA-binding
Biological processTranscription, Transcription regulation

Enzyme and pathway databases

SignaLinkiQ9UIU6
SIGNORiQ9UIU6

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX4
Alternative name(s):
Sine oculis homeobox homolog 4
Gene namesi
Name:SIX4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

EuPathDBiHostDB:ENSG00000100625.8
HGNCiHGNC:10890 SIX4
MIMi606342 gene
neXtProtiNX_Q9UIU6

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

Organism-specific databases

OpenTargetsiENSG00000100625
PharmGKBiPA35790

Polymorphism and mutation databases

BioMutaiSIX4
DMDMi254763333

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000493032 – 781Homeobox protein SIX4Add BLAST780

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei640PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ9UIU6
MaxQBiQ9UIU6
PaxDbiQ9UIU6
PeptideAtlasiQ9UIU6
PRIDEiQ9UIU6
ProteomicsDBi84568

PTM databases

iPTMnetiQ9UIU6
PhosphoSitePlusiQ9UIU6

Expressioni

Gene expression databases

BgeeiENSG00000100625
CleanExiHS_SIX4
ExpressionAtlasiQ9UIU6 baseline and differential
GenevisibleiQ9UIU6 HS

Organism-specific databases

HPAiHPA031794

Interactioni

Subunit structurei

Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein.By similarity

Protein-protein interaction databases

BioGridi119730, 7 interactors
IntActiQ9UIU6, 2 interactors
MINTiQ9UIU6
STRINGi9606.ENSP00000216513

Structurei

3D structure databases

ProteinModelPortaliQ9UIU6
SMRiQ9UIU6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi36 – 102Ala-richAdd BLAST67

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiKOG0775 Eukaryota
ENOG410XRPB LUCA
GeneTreeiENSGT00540000070251
HOGENOMiHOG000261651
HOVERGENiHBG017802
InParanoidiQ9UIU6
KOiK15615
OMAiPVYMQQI
OrthoDBiEOG091G083I
PhylomeDBiQ9UIU6
TreeFamiTF315545

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR017970 Homeobox_CS
IPR001356 Homeobox_dom
IPR031701 SIX1_SD
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

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9UIU6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSSSPTGQI ASAADIKQEN GMESASEGQE AHREVAGGAA VGLSPPAPAP
60 70 80 90 100
FPLEPGDAAT AAARVSGEEG AVAAAAAGAA ADQVQLHSEL LGRHHHAAAA
110 120 130 140 150
AAQTPLAFSP DHVACVCEAL QQGGNLDRLA RFLWSLPQSD LLRGNESLLK
160 170 180 190 200
ARALVAFHQG IYPELYSILE SHSFESANHP LLQQLWYKAR YTEAERARGR
210 220 230 240 250
PLGAVDKYRL RRKFPLPRTI WDGEETVYCF KEKSRNALKE LYKQNRYPSP
260 270 280 290 300
AEKRHLAKIT GLSLTQVSNW FKNRRQRDRN PSETQSKSES DGNPSTEDES
310 320 330 340 350
SKGHEDLSPH PLSSSSDGIT NLSLSSHMEP VYMQQIGNAK ISLSSSGVLL
360 370 380 390 400
NGSLVPASTS PVFLNGNSFI QGPSGVILNG LNVGNTQAVA LNPPKMSSNI
410 420 430 440 450
VSNGISMTDI LGSTSQDVKE FKVLQSSANS ATTTSYSPSV PVSFPGLIPS
460 470 480 490 500
TEVKREGIQT VASQDGGSVV TFTTPVQINQ YGIVQIPNSG ANSQFLNGSI
510 520 530 540 550
GFSPLQLPPV SVAASQGNIS VSSSTSDGST FTSESTTVQQ GKVFLSSLAP
560 570 580 590 600
SAVVYTVPNT GQTIGSVKQE GLERSLVFSQ LMPVNQNAQV NANLSSENIS
610 620 630 640 650
GSGLHPLASS LVNVSPTHNF SLSPSTLLNP TELNRDIADS QPMSAPVASK
660 670 680 690 700
STVTSVSNTN YATLQNCSLI TGQDLLSVPM TQAALGEIVP TAEDQVGHPS
710 720 730 740 750
PAVHQDFVQE HRLVLQSVAN MKENFLSNSE SKATSSLMML DSKSKYVLDG
760 770 780
MVDTVCEDLE TDKKELAKLQ TVQLDEDMQD L
Length:781
Mass (Da):82,933
Last modified:July 28, 2009 - v2
Checksum:i0054080AFF7BFF7E
GO

Sequence cautioni

The sequence BAA86223 differs from that shown. Reason: Erroneous initiation.Curated
The sequence EAW80786 differs from that shown. Reason: Erroneous initiation.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03644123E → Q in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_036442446G → D in a breast cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs750515774Ensembl.1
Natural variantiVAR_058281605H → P2 PublicationsCorresponds to variant dbSNP:rs3742636Ensembl.1
Natural variantiVAR_036443780D → E in a breast cancer sample; somatic mutation. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB024687 Genomic DNA Translation: BAA86223.1 Different initiation.
AL132777 Genomic DNA No translation available.
CH471061 Genomic DNA Translation: EAW80786.1 Different initiation.
BC098135 mRNA Translation: AAH98135.1
BC098282 mRNA Translation: AAH98282.1
BC099722 mRNA Translation: AAH99722.1
BC101934 mRNA Translation: AAI01935.1
CCDSiCCDS9749.2
RefSeqiNP_059116.3, NM_017420.4
UniGeneiHs.690393
Hs.97849

Genome annotation databases

EnsembliENST00000216513; ENSP00000216513; ENSG00000100625
GeneIDi51804
KEGGihsa:51804
UCSCiuc001xfc.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiSIX4_HUMAN
AccessioniPrimary (citable) accession number: Q9UIU6
Secondary accession number(s): Q4QQH5, Q4V764
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: July 28, 2009
Last modified: June 20, 2018
This is version 142 of the entry and version 2 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

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. SIMILARITY comments
    Index of protein domains and families

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