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68  structures 438  species 0  interactions 6859  sequences 73  architectures

Family: T-box (PF00907)

Summary: T-box

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T-box Edit Wikipedia article

Crystallographic structure of the TBX3 protein dimer (cyan and green) complexed with DNA (brown) based on the PDB: 1h6f​ coordinates.

T-box refers to a group of transcription factors involved in embryonic limb and heart development.[1] Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.[2]

Mutations in the first one found caused short tails in mice, and thus the protein encoded was named brachyury, Greek for "short-tail". In mice this gene is named "T", but in humans it is named "TBXT".[3][4] Brachyury has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.[5]

The mouse T gene was cloned,[6] and proved that brachyury was a 436 amino acid embryonic nuclear transcription factor. Brachyury binds to the T-box, through a region at its N-terminus.

Protein activity

The encoded proteins of Tbx5 and Tbx4 play a role in limb development, and play a major role in limb bud initiation specifically.[7] For instance, in chickens Tbx4 specifies hindlimb status while Tbx5 specifies forelimb status.[8] The activation of these proteins by Hox genes initiates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds.[7] Ultimately, Tbx4 and Tbx5 lead to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.[7] Together, Tbx5 and Tbx4 play a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[9]


In humans, and some other animals, defects in the TBX5 gene expression are responsible for Holt-Oram syndrome, which is characterized by at least one abnormal wrist bone. Other arm bones are almost always affected, though the severity can vary widely, from complete absence of a bone, to only a reduction in bone length.[10][11] Seventy-five percent of affected individuals also have heart defects, most often there is no separation between the left and right ventricle of the heart.[12]

TBX3 is associated with ulnar-mammary syndrome in humans, but is also responsible for the presence or absence of dun color in horses, and has no deleterious effects whether expressed or not.[13]

T-box genes

Genes encoding T-box proteins include:

See also


  1. ^ Wilson V, Conlon FL (2002). "The T-box family". Genome Biology. 3 (6): REVIEWS3008. doi:10.1186/gb-2002-3-6-reviews3008. PMC 139375. PMID 12093383.
  2. ^ Müller, CW; Herrmann, BG (23 October 1997). "Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor". Nature. 389 (6653): 884–8. doi:10.1038/39929. PMID 9349824.
  3. ^ "Entrez Gene: T".
  4. ^ Edwards YH, Putt W, Lekoape KM, Stott D, Fox M, Hopkinson DA, Sowden J (March 1996). "The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27". Genome Research. 6 (3): 226–33. doi:10.1101/gr.6.3.226. PMID 8963900.
  5. ^ Scholz CB, Technau U (January 2003). "The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa)". Development Genes and Evolution. 212 (12): 563–70. doi:10.1007/s00427-002-0272-x. PMID 12536320.
  6. ^ Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H (February 1990). "Cloning of the T gene required in mesoderm formation in the mouse". Nature. 343 (6259): 617–22. Bibcode:1990Natur.343..617H. doi:10.1038/343617a0. PMID 2154694.
  7. ^ a b c Tickle C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–30. doi:10.1111/joa.12361. PMC 4580101. PMID 26249743.
  8. ^ Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (April 1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–8. doi:10.1038/19769. PMID 10235264.
  9. ^ Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP (January 2010). "Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning". Developmental Cell. 18 (1): 148–56. doi:10.1016/j.devcel.2009.11.013. PMC 3034643. PMID 20152185.
  10. ^ "Holt-Oram syndrome". Genetics Home Reference. U.S. National Library of Medicine. June 2014. Retrieved 18 April 2018.
  11. ^ McDermott DA, Fong JC, Basson CT. Holt-Oram Syndrome. 2004 Jul 20 [Updated 2015 Oct 8]. In Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
  12. ^ Bossert, T; Walther, T; Gummert, J; Hubald, R; Kostelka, M; Mohr, FW (October 2002). "Cardiac malformations associated with the Holt-Oram syndrome—report on a family and review of the literature". The Thoracic and cardiovascular surgeon. 50 (5): 312–4. doi:10.1055/s-2002-34573. PMID 12375192. Retrieved 7 November 2012.
  13. ^ Imsland F, McGowan K, Rubin CJ, Henegar C, Sundström E, Berglund J, et al. (February 2016). "Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses". Nature Genetics. 48 (2): 152–8. doi:10.1038/ng.3475. PMC 4731265. PMID 26691985. Lay summary – Science Daily.

Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

T-box Provide feedback

The T-box encodes a 180 amino acid domain that binds to DNA. Genes encoding T-box proteins are found in a wide range of animals, but not in other kingdoms such as plants. Family members are all thought to bind to the DNA consensus sequence TCACACCT. they are found exclusively in the nucleus, and perform DNA-binding and transcriptional activation/repression roles. They are generally required for development of the specific tissues they are expressed in, and mutations in T-box genes are implicated in human conditions such as DiGeorge syndrome and X-linked cleft palate, which feature malformations [2].

Literature references

  1. Muller CW, Herrmann BG; , Nature 1997;389:884-888.: Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor. PUBMED:9349824 EPMC:9349824

  2. Wilson V, Conlon FL; , Genome Biol 2002;3:REVIEWS3008.: The T-box family. PUBMED:12093383 EPMC:12093383

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001699

Transcription factors of the T-box family are required both for early cell-fate decisions, such as those necessary for formation of the basic vertebrate body plan, and for differentiation and organogenesis [ PUBMED:12093383 ]. The T-box is defined as the minimal region within the T-box protein that is both necessary and sufficient for sequence-specific DNA binding, all members of the family so far examined bind to the DNA consensus sequence TCACACCT. The T-box is a relatively large DNA-binding domain, generally comprising about a third of the entire protein (17-26kDa) [ PUBMED:9349824 ].

These genes were uncovered on the basis of similarity to the DNA binding domain [ PUBMED:9504043 ] of Mus musculus (Mouse) Brachyury (T) gene product, which similarity is the defining feature of the family. The Brachyury gene is named for its phenotype, which was identified 70 years ago as a mutant mouse strain with a short blunted tail. The gene, and its paralogues, have become a well-studied model for the family, and hence much of what is known about the T-box family is derived from the murine Brachyury gene.

Consistent with its nuclear location, Brachyury protein has a sequence-specific DNA-binding activity and can act as a transcriptional regulator [ PUBMED:9503012 ]. Homozygous mutants for the gene undergo extensive developmental anomalies, thus rendering the mutation lethal [ PUBMED:9395282 ]. The postulated role of Brachyury is as a transcription factor, regulating the specification and differentiation of posterior mesoderm during gastrulation in a dose-dependent manner [ PUBMED:9504043 ].

T-box proteins tend to be expressed in specific organs or cell types, especially during development, and they are generally required for the development of those tissues, for example, Brachyury is expressed in posterior mesoderm and in the developing notochord, and it is required for the formation of these cells in mice [ PUBMED:9196325 ].

The T-box family is an ancient group that appears to play a critical role in development in all animal species [ PUBMED:7920656 ].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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Pfam Clan

This family is a member of clan P53-like (CL0073), which has the following description:

This clan contains a variety of DNA-binding domains that contain an immunoglobulin-like fold. It includes the DNA-binding domains of NF-kappaB, NFAT, p53, STAT-1, the T-domain and the Runt domain [1].

The clan contains the following 9 members:

CEP1-DNA_bind LAG1-DNAbind NDT80_PhoG P53 PAD_M RHD_DNA_bind Runt STAT_bind T-box


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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_363 (release 3.0)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 108
Number in full: 6859
Average length of the domain: 162.90 aa
Average identity of full alignment: 49 %
Average coverage of the sequence by the domain: 29.43 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.5 20.5
Noise cut-off 20.4 20.4
Model length: 185
Family (HMM) version: 24
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Species distribution

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the T-box domain has been found. There are 68 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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