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Q99081 (HTF4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Transcription factor 12

Short name=TCF-12
Alternative name(s):
Class B basic helix-loop-helix protein 20
Short name=bHLHb20
DNA-binding protein HTF4
E-box-binding protein
Transcription factor HTF-4
Gene names
Name:TCF12
Synonyms:BHLHB20, HEB, HTF4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length682 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3').

Subunit structure

Efficient DNA binding requires dimerization with another bHLH protein. Forms homo- or heterooligomers with myogenin, E12 and ITF2 proteins. Interacts with PTF1A. Interacts with NEUROD2 By similarity. Interacts with RUNX1T1. Ref.9 Ref.18

Subcellular location

Nucleus.

Tissue specificity

Expressed in several tissues and cell types including skeletal muscle, thymus, and a B-cell line.

Domain

the 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. Ref.11

Involvement in disease

Craniosynostosis 3 (CRS3) [MIM:615314]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.19

Sequence similarities

Contains 1 bHLH (basic helix-loop-helix) domain.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q99081-1)

Also known as: a;

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.
Isoform 2 (identifier: Q99081-2)

Also known as: b;

The sequence of this isoform differs from the canonical sequence as follows:
     1-170: Missing.
     171-193: DSAALDPLQAKKVRKVPPGLPSS → MYCAYPVPGMGSNSLMYYYNGKT
Isoform 3 (identifier: Q99081-3)

Also known as: c;

The sequence of this isoform differs from the canonical sequence as follows:
     396-396: L → LKNRVEQQLHEHLQDAMSFLKDVCE

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 682682Transcription factor 12
PRO_0000127228

Regions

Domain577 – 63054bHLH
Region119 – 14022Leucine-zipper
Region632 – 65524Class A specific domain
Motif19 – 2799aaTAD

Amino acid modifications

Modified residue671Phosphoserine Ref.15
Modified residue3131Phosphothreonine Ref.14
Modified residue3331Phosphoserine Ref.15
Modified residue5571Phosphothreonine Ref.15
Modified residue5591Phosphoserine Ref.17

Natural variations

Alternative sequence1 – 170170Missing in isoform 2.
VSP_039109
Alternative sequence171 – 19323DSAAL…GLPSS → MYCAYPVPGMGSNSLMYYYN GKT in isoform 2.
VSP_039110
Alternative sequence3961L → LKNRVEQQLHEHLQDAMSFL KDVCE in isoform 3.
VSP_040024
Natural variant3001G → S.
Corresponds to variant rs12442879 [ dbSNP | Ensembl ].
VAR_049543
Natural variant6001L → P in CRS3. Ref.19
VAR_070096
Natural variant6141Q → E in CRS3. Ref.19
VAR_070097

Experimental info

Sequence conflict5231K → E in CAD89914. Ref.3

Secondary structure

..... 682
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (a) [UniParc].

Last modified October 1, 1996. Version 1.
Checksum: 9736113D9361D3F5

FASTA68272,965
        10         20         30         40         50         60 
MNPQQQRMAA IGTDKELSDL LDFSAMFSPP VNSGKTRPTT LGSSQFSGSG IDERGGTTSW 

        70         80         90        100        110        120 
GTSGQPSPSY DSSRGFTDSP HYSDHLNDSR LGAHEGLSPT PFMNSNLMGK TSERGSFSLY 

       130        140        150        160        170        180 
SRDTGLPGCQ SSLLRQDLGL GSPAQLSSSG KPGTAYYSFS ATSSRRRPLH DSAALDPLQA 

       190        200        210        220        230        240 
KKVRKVPPGL PSSVYAPSPN SDDFNRESPS YPSPKPPTSM FASTFFMQDG THNSSDLWSS 

       250        260        270        280        290        300 
SNGMSQPGFG GILGTSTSHM SQSSSYGNLH SHDRLSYPPH SVSPTDINTS LPPMSSFHRG 

       310        320        330        340        350        360 
STSSSPYVAA SHTPPINGSD SILGTRGNAA GSSQTGDALG KALASIYSPD HTSSSFPSNP 

       370        380        390        400        410        420 
STPVGSPSPL TGTSQWPRPG GQAPSSPSYE NSLHSLQSRM EDRLDRLDDA IHVLRNHAVG 

       430        440        450        460        470        480 
PSTSLPAGHS DIHSLLGPSH NAPIGSLNSN YGGSSLVASS RSASMVGTHR EDSVSLNGNH 

       490        500        510        520        530        540 
SVLSSTVTTS STDLNHKTQE NYRGGLQSQS GTVVTTEIKT ENKEKDENLH EPPSSDDMKS 

       550        560        570        580        590        600 
DDESSQKDIK VSSRGRTSST NEDEDLNPEQ KIEREKERRM ANNARERLRV RDINEAFKEL 

       610        620        630        640        650        660 
GRMCQLHLKS EKPQTKLLIL HQAVAVILSL EQQVRERNLN PKAACLKRRE EEKVSAVSAE 

       670        680 
PPTTLPGTHP GLSETTNPMG HM 

« Hide

Isoform 2 (b) [UniParc].

Checksum: 98AF7F83F8A2AEF4
Show »

FASTA51255,142
Isoform 3 (c) [UniParc].

Checksum: 75B7B4173C9B660D
Show »

FASTA70675,845

References

« Hide 'large scale' references
[1]"The nucleotide sequence of the human transcription factor HTF4a cDNA."
Zhang Y., Bina M.
DNA Seq. 2:397-403(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors."
Hu J.S., Olson E.N., Kingston R.E.
Mol. Cell. Biol. 12:1031-1042(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Skeletal muscle.
[3]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Tissue: Endometrium and Skeletal muscle.
[4]"Analysis of the DNA sequence and duplication history of human chromosome 15."
Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A. expand/collapse author list , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"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] (ISOFORM 3).
Tissue: Brain.
[7]"HTF4: a new human helix-loop-helix protein."
Zhang Y., Babin J., Feldhaus A.L., Singh H., Sharp P.A., Bina M.
Nucleic Acids Res. 19:4555-4555(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 352-682.
[8]"Genomic organization of human TCF12 gene and spliced mRNA variants producing isoforms of transcription factor HTF4."
Gan T.I., Rowen L., Nesbitt R., Roe B.A., Wu H., Hu P., Yao Z., Kim U.J., O'Sickey T., Bina M.
Cytogenet. Genome Res. 98:245-248(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: GENE ORGANIZATION, ALTERNATIVE SPLICING.
[9]"The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity."
Liu Y., Cheney M.D., Gaudet J.J., Chruszcz M., Lukasik S.M., Sugiyama D., Lary J., Cole J., Dauter Z., Minor W., Speck N.A., Bushweller J.H.
Cancer Cell 9:249-260(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RUNX1T1.
[10]"A probability-based approach for high-throughput protein phosphorylation analysis and site localization."
Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.
Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"Nine-amino-acid transactivation domain: establishment and prediction utilities."
Piskacek S., Gregor M., Nemethova M., Grabner M., Kovarik P., Piskacek M.
Genomics 89:756-768(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN.
[12]"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage."
Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.
Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic kidney.
[13]"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[14]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-313, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[15]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-67; SER-333 AND THR-557, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[16]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[17]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-559, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]"Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity."
Park S., Chen W., Cierpicki T., Tonelli M., Cai X., Speck N.A., Bushweller J.H.
Blood 113:3558-3567(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 11-28 IN COMPLEX WITH RUNX1T1, SUBUNIT.
[19]"Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis."
500 Whole-Genome Sequences (WGS500) Consortium
Sharma V.P., Fenwick A.L., Brockop M.S., McGowan S.J., Goos J.A., Hoogeboom A.J., Brady A.F., Jeelani N.O., Lynch S.A., Mulliken J.B., Murray D.J., Phipps J.M., Sweeney E., Tomkins S.E., Wilson L.C., Bennett S., Cornall R.J., Broxholme J. expand/collapse author list , Kanapin A., Johnson D., Wall S.A., van der Spek P.J., Mathijssen I.M., Maxson R.E., Twigg S.R., Wilkie A.O.
Nat. Genet. 45:304-307(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS CRS3 PRO-600 AND GLU-614.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M83233 mRNA. Translation: AAB62389.1.
M80627 mRNA. Translation: AAA58632.1.
AL831981 mRNA. Translation: CAD89914.1.
BX537967 mRNA. Translation: CAD97931.1.
AC010999 Genomic DNA. No translation available.
AC016525 Genomic DNA. No translation available.
AC090511 Genomic DNA. No translation available.
AC090532 Genomic DNA. No translation available.
CH471082 Genomic DNA. Translation: EAW77512.1.
BC050556 mRNA. Translation: AAH50556.1.
M65209 mRNA. Translation: AAC37571.1.
BK001049 mRNA. Translation: DAA01129.1.
PIRA42121.
RefSeqNP_003196.1. NM_003205.3.
NP_996919.1. NM_207036.1.
NP_996920.1. NM_207037.1.
NP_996921.1. NM_207038.1.
NP_996923.1. NM_207040.1.
UniGeneHs.511504.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2KNHNMR-B11-28[»]
4JOLX-ray2.91E/F/G/H177-200[»]
ProteinModelPortalQ99081.
SMRQ99081. Positions 578-637.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112798. 27 interactions.
DIPDIP-29403N.
IntActQ99081. 12 interactions.
MINTMINT-4713897.
STRING9606.ENSP00000331057.

Polymorphism databases

DMDM1708332.

Proteomic databases

PaxDbQ99081.
PRIDEQ99081.

Protocols and materials databases

DNASU6938.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000267811; ENSP00000267811; ENSG00000140262. [Q99081-1]
ENST00000333725; ENSP00000331057; ENSG00000140262. [Q99081-3]
ENST00000343827; ENSP00000342459; ENSG00000140262. [Q99081-2]
ENST00000438423; ENSP00000388940; ENSG00000140262. [Q99081-3]
ENST00000557843; ENSP00000453737; ENSG00000140262. [Q99081-1]
GeneID6938.
KEGGhsa:6938.
UCSCuc002aea.3. human. [Q99081-3]
uc002aec.3. human. [Q99081-1]
uc002aee.3. human. [Q99081-2]

Organism-specific databases

CTD6938.
GeneCardsGC15P057210.
HGNCHGNC:11623. TCF12.
HPACAB004432.
HPA002103.
MIM600480. gene.
615314. phenotype.
neXtProtNX_Q99081.
Orphanet209916. Extraskeletal myxoid chondrosarcoma.
35099. Isolated brachycephaly.
35098. Isolated plagiocephaly.
PharmGKBPA36381.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG282899.
HOGENOMHOG000234180.
HOVERGENHBG003854.
KOK15603.
OMAYYSFSAT.
OrthoDBEOG72G16Q.
PhylomeDBQ99081.
TreeFamTF321672.

Enzyme and pathway databases

ReactomeREACT_111045. Developmental Biology.

Gene expression databases

ArrayExpressQ99081.
BgeeQ99081.
CleanExHS_TCF12.
GenevestigatorQ99081.

Family and domain databases

Gene3D4.10.280.10. 1 hit.
InterProIPR011598. bHLH_dom.
[Graphical view]
PfamPF00010. HLH. 1 hit.
[Graphical view]
SMARTSM00353. HLH. 1 hit.
[Graphical view]
SUPFAMSSF47459. SSF47459. 1 hit.
PROSITEPS50888. BHLH. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSTCF12. human.
EvolutionaryTraceQ99081.
GeneWikiTCF12.
GenomeRNAi6938.
NextBio27145.
PROQ99081.
SOURCESearch...

Entry information

Entry nameHTF4_HUMAN
AccessionPrimary (citable) accession number: Q99081
Secondary accession number(s): Q7Z3D9, Q86TC1, Q86VM2
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 129 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM