Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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FH FORKHEAD

SMART accession number:	SM00339
Description:	FORKHEAD, also known as a "winged helix"
Interpro abstract (IPR001766):	The fork head protein of Drosophila melanogaster, a transcription factor that promotes terminal rather than segmental development, contains neither homeodomains nor zinc-fingers characteristic of other transcription factors [(PUBMED:2566386)]. Instead, it contains a distinct type of DNA-binding region, containing around 100 amino acids, which has since been identified in a number of transcription factors (including D. melanogaster FD1-5, mammalian HNF-3, human HTLF, Saccharomyces cerevisiae HCM1, etc.). This is referred to as the fork head domain but is also known as a 'winged helix' [(PUBMED:2566386), (PUBMED:8332212), (PUBMED:1356269)]. The fork head domain binds B-DNA as a monomer [(PUBMED:8332212)], but shows no similarity to previously identified DNA-binding motifs. Although the domain is found in several different transcription factors, a common function is their involvement in early developmental decisions of cell fates during embryogenesis [(PUBMED:1356269)].
GO process:	regulation of transcription, DNA-dependent (GO:0006355)
GO function:	sequence-specific DNA binding (GO:0043565), sequence-specific DNA binding transcription factor activity (GO:0003700)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 2420 FH domains in 2416 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a FH domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with FH domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: DNA-BINDING

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Kaufmann E, Knochel W
  • Five years on the wings of fork head.
  • Mech Dev. 1996; 57: 3-20
  • Display abstract

  • Since its discovery five years ago the conserved family of fork head/HNF-3-related transcription factors has gained increasing importance for the analysis of gene regulatory mechanisms during embryonic development and in differentiated cells. Different members of this family, which is defined by a conserved 110 amino acid residues encompassing DNA binding domain of winged helix structure, serve as regulatory keys in embryogenesis, in tumorigenesis or in the maintenance of differentiated cell states. The purpose of this review is to summarize the accumulating amount of data on structure, expression and function of fork head/HNF-3-related transcription factors.

  • Clark KL, Halay ED, Lai E, Burley SK
  • Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5.
  • Nature. 1993; 364: 412-20
  • Display abstract

  • The three-dimensional structure of an HNF-3/fork head DNA-recognition motif complexed with DNA has been determined by X-ray crystallography at 2.5 A resolution. This alpha/beta protein binds B-DNA as a monomer, through interactions with the DNA backbone and through both direct and water-mediated major and minor groove base contacts, inducing a 13 degrees bend. The transcription factor fold is very similar to the structure of histone H5. In its amino-terminal half, three alpha-helices adopt a compact structure that presents the third helix to the major groove. The remainder of the protein includes a twisted, antiparallel beta-structure and random coil that interacts with the minor groove.

  • Weigel D, Jackle H
  • The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?
  • Cell. 1990; 63: 455-6
• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the FH domain.

  Protein	Disease
  Forkhead box protein E1 (O00358) (SMART)	OMIM:602617: Bamforth-Lazarus syndrome OMIM:241850:
  Forkhead box protein N1 (O15353) (SMART)	OMIM:600838: T-cell immunodeficiency, congenital alopecia, and nail dystrophy
  Forkhead box protein C1 (Q12948) (SMART)	OMIM:601090: Iridogoniodysgenesis OMIM:601631: Anterior segment mesenchymal dysgenesis ; Rieger anomaly ; Axenfeld anomaly ; Iris hypoplasia and glaucoma

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 45.71 map04950 Maturity onset diabetes of the young 25.71 map04910 Insulin signaling pathway 25.71 map05215 Prostate cancer 2.86 map00190 Oxidative phosphorylation This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with FH domain which could be assigned to a KEGG orthologous group, and not all proteins containing FH domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of FH domains in PDB

  PDB code	Main view	Title
  1d5v		Solution structure of the forkhead domain of the adipocyte- transcription factor freac-11 (s12)
  1e17		Solution structure of the dna binding domain of the human forkhead transcription factor afx (foxo4)
  1jxs		Solution structure of the dna-binding domain of interleukin enhancer binding factor
  1kq8		Solution structure of winged helix protein hfh-1
  2a07		Crystal structure of foxp2 bound specifically to dna.
  2a3s		Solution structure and dynamics of dna-binding domain of myocyte nuclear factor
  2as5		Structure of the dna binding domains of nfat and foxp2 bound specifically to dna.
  2c6y		Crystal structure of interleukin enhancer-binding factor 1 bound to dna
  2d2w		Solution structure and dynamics of the dna-binding domain of myocyte nuclear factor
  2hdc		Structure of transcription factor genesis/dna complex
  2hfh		The nmr structures of a winged helix protein: genesis, 20 structures
  2k86		Solution structure of foxo3a forkhead domain
  2uzk		Crystal structure of the human foxo3a-dbd bound to dna
  3bpy		Crystal structure of the dna binding domain of foxo4 bound to dna
  3co6		Crystal structure of foxo1 dbd bound to dbe1 dna
  3co7		Crystal structure of foxo1 dbd bound to dbe2 dna
  3coa		Crystal structure of foxo1 dbd bound to ire dna
  3g73		Structure of the foxm1 dna binding

• Links (links to other resources describing this domain)

• PFAM	Fork_head
  INTERPRO	IPR001766
  PROSITE	FORK_HEAD_3

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