TCF4

Protein identityUniProt · HPA

UniProt accession

P15884

Gene

TCF4

Ensembl

ENSG00000196628

Chromosome

18

Canonical length

667 aa

Protein class

Disease related genes, Human disease related genes, Predicted intracellular proteins, Predicted secreted proteins, Transcription factors

Subcellular location

Nucleoplasm,Cytosol

Secretome location

Secreted - unknown location

OverviewNCBI Gene

This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

Canonical amino-acid sequenceUniProt

667 residues, UniProt reviewed canonical sequence.

>P15884|TCF4
     1  MHHQQRMAAL GTDKELSDLL DFSAMFSPPV SSGKNGPTSL ASGHFTGSNV EDRSSSGSWG
    61  NGGHPSPSRN YGDGTPYDHM TSRDLGSHDN LSPPFVNSRI QSKTERGSYS SYGRESNLQG
   121  CHQQSLLGGD MDMGNPGTLS PTKPGSQYYQ YSSNNPRRRP LHSSAMEVQT KKVRKVPPGL
   181  PSSVYAPSAS TADYNRDSPG YPSSKPATST FPSSFFMQDG HHSSDPWSSS SGMNQPGYAG
   241  MLGNSSHIPQ SSSYCSLHPH ERLSYPSHSS ADINSSLPPM STFHRSGTNH YSTSSCTPPA
   301  NGTDSIMANR GSGAAGSSQT GDALGKALAS IYSPDHTNNS FSSNPSTPVG SPPSLSAGTA
   361  VWSRNGGQAS SSPNYEGPLH SLQSRIEDRL ERLDDAIHVL RNHAVGPSTA MPGGHGDMHG
   421  IIGPSHNGAM GGLGSGYGTG LLSANRHSLM VGTHREDGVA LRGSHSLLPN QVPVPQLPVQ
   481  SATSPDLNPP QDPYRGMPPG LQGQSVSSGS SEIKSDDEGD ENLQDTKSSE DKKLDDDKKD
   541  IKSITSNNDD EDLTPEQKAE REKERRMANN ARERLRVRDI NEAFKELGRM VQLHLKSDKP
   601  QTKLLILHQA VAVILSLEQQ VRERNLNPKA ACLKRREEEK VSSEPPPLSL AGPHPGMGDA
   661  SNHMGQM

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against TCF4 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.68

Highest tissue expression

27 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about TCF4.

Disease | AllUniProt

Conditions TCF4 is implicated in, by any mechanism.

• Pitt-Hopkins syndrome (PTHS) MIM:610954
• Corneal dystrophy, Fuchs endothelial, 3 (FECD3) MIM:613267

Disease | GeneticClinVar

286 pathogenic / likely-pathogenic of 1,272 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Pitt-Hopkins syndrome
• Inborn genetic diseases
• Corneal dystrophy, Fuchs endothelial, 3
• TCF4-related disorder
• Intellectual disability

ReferencesPubMed · IEDB

Publications for TCF4 from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.22

gnomAD pLI

1

gnomAD missense Z

4.1

DepMap mean gene effect

0.09

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• cell differentiation
• nervous system development
• positive regulation of DNA-templated transcription
• positive regulation of neuron differentiation
• positive regulation of transcription by RNA polymerase II
• protein-DNA complex assembly
• regulation of transcription by RNA polymerase II

Molecular functions

• beta-catenin binding
• DNA binding
• DNA-binding transcription activator activity, RNA polymerase II-specific
• DNA-binding transcription factor activity
• DNA-binding transcription factor activity, RNA polymerase II-specific
• E-box binding
• identical protein binding
• protein heterodimerization activity
• RNA polymerase II cis-regulatory region sequence-specific DNA binding
• sequence-specific double-stranded DNA binding
• TFIIB-class transcription factor binding

Cellular components

• beta-catenin-TCF complex
• beta-catenin-TCF7L2 complex
• chromatin
• nucleus
• transcription regulator complex

Protein domainsUniProt · Pfam · InterPro

• Myc-type, basic helix-loop-helix (bHLH) domain
• Helix-loop-helix DNA-binding domain superfamily
• Neuronal Differentiation E-box Binding Transcription Factors
• Helix-loop-helix DNA-binding domain

KeywordsUniProt

• Activator
• Corneal dystrophy
• Differentiation
• DNA-binding
• Epilepsy
• Intellectual disability
• Neurogenesis
• Nucleus
• Phosphoprotein
• Primary microcephaly
• Transcription
• Transcription regulation

InteractionsUniProt · HPA

Protein binding partners of TCF4 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• AGBL1
• BHLHA9
• HIVEP2
• NEUROD2
• SOX17
• CBFA2T2
• ASCL1
• CABP5
• CTNNB1
• FERD3L
• GORASP2
• HAND2
• ID1
• ID2
• ID3
• NEK6
• NEUROG1
• SGF29
• TAL1
• TAL2
• TP53
• TWIST1
• TWIST2