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Protein

Homeobox protein Nkx-2.1

Gene

NKX2-1

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

Functioni

Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1 (By similarity).By similarity

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi161 – 220HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

  • core promoter binding Source: UniProtKB
  • DNA binding Source: UniProtKB
  • enzyme binding Source: UniProtKB
  • intronic transcription regulatory region DNA binding Source: MGI
  • intronic transcription regulatory region sequence-specific DNA binding Source: UniProtKB
  • RNA polymerase II regulatory region DNA binding Source: MGI
  • RNA polymerase II regulatory region sequence-specific DNA binding Source: MGI
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Source: Ensembl
  • transcription factor activity, sequence-specific DNA binding Source: UniProtKB
  • transcription regulatory region DNA binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator, Repressor

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

SIGNORiP43699.

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein Nkx-2.1
Alternative name(s):
Homeobox protein NK-2 homolog A
Thyroid nuclear factor 1
Thyroid transcription factor 1
Short name:
TTF-1
Thyroid-specific enhancer-binding protein
Short name:
T/EBP
Gene namesi
Name:NKX2-1Imported
Synonyms:NKX2A, TITF1, TTF1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:11825. NKX2-1.

Subcellular locationi

  • Nucleus By similarity

GO - Cellular componenti

  • nucleoplasm Source: UniProtKB
  • nucleus Source: UniProtKB
  • transcription factor complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Chorea, hereditary benign (BHC)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare autosomal dominant movement disorder, defined by early onset in childhood, a stable or non-progressive course of chorea, and no mental deterioration. Chorea is characterized by involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement.
See also OMIM:118700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075209172Q → H in BHC; decrease in DNA-binding; no effect on transcription activation from thyroglobulin/TG, nor from pulmonary surfactant-associated protein C/SFTPC gene promoters. 1 Publication1
Natural variantiVAR_015188208W → L in BHC. 1 PublicationCorresponds to variant rs28936672dbSNPEnsembl.1
Natural variantiVAR_075210208W → S in BHC; loss of transcription activation. 1 Publication1
Natural variantiVAR_015189213R → S in BHC. 1 PublicationCorresponds to variant rs28936671dbSNPEnsembl.1
Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant disorder that manifests in infancy with neurological disturbances, hypothyroidism, and respiratory problems. It is characterized by movement abnormalities beginning with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria.
See also OMIM:610978
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_073040203T → R in CAHTP. 1 Publication1
Natural variantiVAR_034906205V → F in CAHTP. 2 PublicationsCorresponds to variant rs137852692dbSNPEnsembl.1
Thyroid cancer, non-medullary, 1 (NMTC1)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms.
See also OMIM:188550
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075769339A → V in NMTC1; loss of transcription regulatory region DNA binding; decreased transcription factor activity, sequence-specific DNA binding; tested for the thyroglobulin gene; associated with dominant impairment of thyroid-specific genes transcription and increased thyroid cells proliferation. 1 PublicationCorresponds to variant rs537209983dbSNPEnsembl.1

Keywords - Diseasei

Congenital hypothyroidism, Disease mutation

Organism-specific databases

DisGeNETi7080.
MalaCardsiNKX2-1.
MIMi118700. phenotype.
188550. phenotype.
610978. phenotype.
OpenTargetsiENSG00000136352.
Orphaneti95713. Athyreosis.
1429. Benign familial chorea.
209905. Brain-lung-thyroid syndrome.
146. Papillary or follicular thyroid carcinoma.
95720. Thyroid hypoplasia.
PharmGKBiPA36531.

Polymorphism and mutation databases

BioMutaiNKX2-1.
DMDMi1174819.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000493431 – 371Homeobox protein Nkx-2.1Add BLAST371

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei254PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated on serine residues by STK3/MST2.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP43699.
PaxDbiP43699.
PeptideAtlasiP43699.
PRIDEiP43699.

PTM databases

iPTMnetiP43699.
PhosphoSitePlusiP43699.

Expressioni

Tissue specificityi

Thyroid and lung.

Gene expression databases

BgeeiENSG00000136352.
CleanExiHS_NKX2-1.
HS_TTF1.
ExpressionAtlasiP43699. baseline and differential.
GenevisibleiP43699. HS.

Organism-specific databases

HPAiCAB000078.
CAB053633.

Interactioni

Subunit structurei

Interacts with WWTR1.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
CCDC59Q9P0314EBI-1391923,EBI-1047110
NCK1P163332EBI-1391923,EBI-389883

GO - Molecular functioni

  • enzyme binding Source: UniProtKB

Protein-protein interaction databases

BioGridi112936. 11 interactors.
IntActiP43699. 8 interactors.
MINTiMINT-192847.
STRINGi9606.ENSP00000346879.

Structurei

3D structure databases

ProteinModelPortaliP43699.
SMRiP43699.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi234 – 243Poly-Gly10
Compositional biasi246 – 253Poly-Gln8
Compositional biasi294 – 303Poly-Ala10

Sequence similaritiesi

Belongs to the NK-2 homeobox family.Curated
Contains 1 homeobox DNA-binding domain.PROSITE-ProRule annotation

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiKOG0842. Eukaryota.
ENOG410XR21. LUCA.
GeneTreeiENSGT00860000133666.
HOGENOMiHOG000231923.
HOVERGENiHBG006689.
InParanoidiP43699.
KOiK09342.
OMAiAMQQHHM.
OrthoDBiEOG091G0LZ2.
PhylomeDBiP43699.
TreeFamiTF351204.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR020479. Homeobox_metazoa.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
PRINTSiPR00024. HOMEOBOX.
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P43699-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSMSPKHTTP FSVSDILSPL EESYKKVGME GGGLGAPLAA YRQGQAAPPT
60 70 80 90 100
AAMQQHAVGH HGAVTAAYHM TAAGVPQLSH SAVGGYCNGN LGNMSELPPY
110 120 130 140 150
QDTMRNSASG PGWYGANPDP RFPAISRFMG PASGMNMSGM GGLGSLGDVS
160 170 180 190 200
KNMAPLPSAP RRKRRVLFSQ AQVYELERRF KQQKYLSAPE REHLASMIHL
210 220 230 240 250
TPTQVKIWFQ NHRYKMKRQA KDKAAQQQLQ QDSGGGGGGG GTGCPQQQQA
260 270 280 290 300
QQQSPRRVAV PVLVKDGKPC QAGAPAPGAA SLQGHAQQQA QHQAQAAQAA
310 320 330 340 350
AAAISVGSGG AGLGAHPGHQ PGSAGQSPDL AHHAASPAAL QGQVSSLSHL
360 370
NSSGSDYGTM SCSTLLYGRT W
Length:371
Mass (Da):38,596
Last modified:November 1, 1995 - v1
Checksum:i5F1E3B40A1BBD862
GO
Isoform 3 (identifier: P43699-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MWSGGSGKARGWEAAAGGRSSPGRLSRRRIM

Show »
Length:401
Mass (Da):41,737
Checksum:i40324D55128D4394
GO

Sequence cautioni

The sequence AAH06221 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA23527 differs from that shown. Reason: Erroneous gene model prediction.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti49P → H in BAA23527 (Ref. 5) Curated1
Sequence conflicti49P → H in BAA23529 (Ref. 5) Curated1
Sequence conflicti61H → P in BAA23527 (Ref. 5) Curated1
Sequence conflicti61H → P in BAA23529 (Ref. 5) Curated1
Sequence conflicti158S → T in BAA23527 (Ref. 5) Curated1
Sequence conflicti158S → T in BAA23529 (Ref. 5) Curated1
Sequence conflicti161R → G in BAA23527 (Ref. 5) Curated1
Sequence conflicti161R → G in BAA23529 (Ref. 5) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075209172Q → H in BHC; decrease in DNA-binding; no effect on transcription activation from thyroglobulin/TG, nor from pulmonary surfactant-associated protein C/SFTPC gene promoters. 1 Publication1
Natural variantiVAR_073040203T → R in CAHTP. 1 Publication1
Natural variantiVAR_034906205V → F in CAHTP. 2 PublicationsCorresponds to variant rs137852692dbSNPEnsembl.1
Natural variantiVAR_015188208W → L in BHC. 1 PublicationCorresponds to variant rs28936672dbSNPEnsembl.1
Natural variantiVAR_075210208W → S in BHC; loss of transcription activation. 1 Publication1
Natural variantiVAR_015189213R → S in BHC. 1 PublicationCorresponds to variant rs28936671dbSNPEnsembl.1
Natural variantiVAR_075769339A → V in NMTC1; loss of transcription regulatory region DNA binding; decreased transcription factor activity, sequence-specific DNA binding; tested for the thyroglobulin gene; associated with dominant impairment of thyroid-specific genes transcription and increased thyroid cells proliferation. 1 PublicationCorresponds to variant rs537209983dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0378901M → MWSGGSGKARGWEAAAGGRS SPGRLSRRRIM in isoform 3. 3 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U19756 mRNA. Translation: AAA86099.1.
X82850 mRNA. Translation: CAA58053.1.
U19816 Genomic DNA. Translation: AAC50125.1.
U33749 mRNA. Translation: AAB52381.1.
U43203 mRNA. Translation: AAA89066.1.
D50739 Genomic DNA. Translation: BAA23527.1. Sequence problems.
D50740 mRNA. Translation: BAA23529.1.
BT009773 mRNA. Translation: AAP88775.1.
AL132857 Genomic DNA. No translation available.
CH471078 Genomic DNA. Translation: EAW65858.1.
CH471078 Genomic DNA. Translation: EAW65856.1.
CH471078 Genomic DNA. Translation: EAW65859.1.
BC006221 mRNA. Translation: AAH06221.2. Different initiation.
CCDSiCCDS41945.1. [P43699-3]
CCDS9659.1. [P43699-1]
PIRiG02321.
RefSeqiNP_001073136.1. NM_001079668.2. [P43699-3]
NP_003308.1. NM_003317.3. [P43699-1]
UniGeneiHs.94367.

Genome annotation databases

EnsembliENST00000354822; ENSP00000346879; ENSG00000136352. [P43699-3]
ENST00000498187; ENSP00000429607; ENSG00000136352. [P43699-1]
ENST00000518149; ENSP00000428341; ENSG00000136352. [P43699-1]
ENST00000522719; ENSP00000429519; ENSG00000136352. [P43699-1]
GeneIDi7080.
KEGGihsa:7080.
UCSCiuc001wtt.4. human. [P43699-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U19756 mRNA. Translation: AAA86099.1.
X82850 mRNA. Translation: CAA58053.1.
U19816 Genomic DNA. Translation: AAC50125.1.
U33749 mRNA. Translation: AAB52381.1.
U43203 mRNA. Translation: AAA89066.1.
D50739 Genomic DNA. Translation: BAA23527.1. Sequence problems.
D50740 mRNA. Translation: BAA23529.1.
BT009773 mRNA. Translation: AAP88775.1.
AL132857 Genomic DNA. No translation available.
CH471078 Genomic DNA. Translation: EAW65858.1.
CH471078 Genomic DNA. Translation: EAW65856.1.
CH471078 Genomic DNA. Translation: EAW65859.1.
BC006221 mRNA. Translation: AAH06221.2. Different initiation.
CCDSiCCDS41945.1. [P43699-3]
CCDS9659.1. [P43699-1]
PIRiG02321.
RefSeqiNP_001073136.1. NM_001079668.2. [P43699-3]
NP_003308.1. NM_003317.3. [P43699-1]
UniGeneiHs.94367.

3D structure databases

ProteinModelPortaliP43699.
SMRiP43699.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112936. 11 interactors.
IntActiP43699. 8 interactors.
MINTiMINT-192847.
STRINGi9606.ENSP00000346879.

PTM databases

iPTMnetiP43699.
PhosphoSitePlusiP43699.

Polymorphism and mutation databases

BioMutaiNKX2-1.
DMDMi1174819.

Proteomic databases

MaxQBiP43699.
PaxDbiP43699.
PeptideAtlasiP43699.
PRIDEiP43699.

Protocols and materials databases

DNASUi7080.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000354822; ENSP00000346879; ENSG00000136352. [P43699-3]
ENST00000498187; ENSP00000429607; ENSG00000136352. [P43699-1]
ENST00000518149; ENSP00000428341; ENSG00000136352. [P43699-1]
ENST00000522719; ENSP00000429519; ENSG00000136352. [P43699-1]
GeneIDi7080.
KEGGihsa:7080.
UCSCiuc001wtt.4. human. [P43699-1]

Organism-specific databases

CTDi7080.
DisGeNETi7080.
GeneCardsiNKX2-1.
HGNCiHGNC:11825. NKX2-1.
HPAiCAB000078.
CAB053633.
MalaCardsiNKX2-1.
MIMi118700. phenotype.
188550. phenotype.
600635. gene.
610978. phenotype.
neXtProtiNX_P43699.
OpenTargetsiENSG00000136352.
Orphaneti95713. Athyreosis.
1429. Benign familial chorea.
209905. Brain-lung-thyroid syndrome.
146. Papillary or follicular thyroid carcinoma.
95720. Thyroid hypoplasia.
PharmGKBiPA36531.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0842. Eukaryota.
ENOG410XR21. LUCA.
GeneTreeiENSGT00860000133666.
HOGENOMiHOG000231923.
HOVERGENiHBG006689.
InParanoidiP43699.
KOiK09342.
OMAiAMQQHHM.
OrthoDBiEOG091G0LZ2.
PhylomeDBiP43699.
TreeFamiTF351204.

Enzyme and pathway databases

SIGNORiP43699.

Miscellaneous databases

GeneWikiiNK2_homeobox_1.
GenomeRNAii7080.
PROiP43699.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000136352.
CleanExiHS_NKX2-1.
HS_TTF1.
ExpressionAtlasiP43699. baseline and differential.
GenevisibleiP43699. HS.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR020479. Homeobox_metazoa.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
PRINTSiPR00024. HOMEOBOX.
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNKX21_HUMAN
AccessioniPrimary (citable) accession number: P43699
Secondary accession number(s): D3DSA3
, O14954, O14955, Q7KZF6, Q9BRJ8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: November 30, 2016
This is version 166 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

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

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 one 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.