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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FHA Forkhead associated domain

SMART accession number:	SM00240
Description:	Found in eukaryotic and prokaryotic proteins. Putative nuclear signalling domain.
Interpro abstract (IPR000253):	The forkhead-associated (FHA) domain [(PUBMED:7482699)] is a phosphopeptide recognition domain found in many regulatory proteins. It displays specificity for phosphothreonine-containing epitopes but will also recognise phosphotyrosine with relatively high affinity. It spans approximately 80-100 amino acid residues folded into an 11-stranded beta sandwich, which sometimes contain small helical insertions between the loops connecting the strands [(PUBMED:11911881)]. To date, genes encoding FHA-containing proteins have been identified in eubacterial and eukaryotic but not archaeal genomes. The domain is present in a diverse range of proteins, such as kinases, phosphatases, kinesins, transcription factors, RNA-binding proteins and metabolic enzymes which partake in many different cellular processes - DNA repair, signal transduction, vesicular transport and protein degradation are just a few examples.
GO function:	protein binding (GO:0005515)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 5457 FHA domains in 5145 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 FHA domain in a specific node, click on it.

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

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

• Cellular role (predicted cellular role)

• Cellular role: signalling
  

• Literature (relevant references for this domain)

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

  • Durocher D, Henckel J, Fersht AR, Jackson SP
  • The FHA domain is a modular phosphopeptide recognition motif.
  • Mol Cell. 1999; 4: 387-94
  • Display abstract

  • FHA domains are conserved sequences of 65-100 amino acid residues found principally within eukaryotic nuclear proteins, but which also exist in certain prokaryotes. The FHA domain is thought to mediate protein-protein interactions, but its mode of action has yet to be elucidated. Here, we show that the two highly divergent FHA domains of Saccharomyces cerevisiae Rad53p, a protein kinase involved in cell cycle checkpoint control, possess phosphopeptide-binding specificity. We also demonstrate that other FHA domains bind peptides in a phospho-dependent manner. These findings indicate that the FHA domain is a phospho-specific protein-protein interaction motif and have important implications for mechanisms of intracellular signaling in both eukaryotes and prokaryotes.

  • Sun Z, Hsiao J, Fay DS, Stern DF
  • Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint.
  • Science. 1998; 281: 272-4
  • Display abstract

  • The Rad53 protein kinase of Saccharomyces cerevisiae is required for checkpoints that prevent cell division in cells with damaged or incompletely replicated DNA. The Rad9 protein was phosphorylated in response to DNA damage, and phosphorylated Rad9 interacted with the COOH-terminal forkhead homology-associated (FHA) domain of Rad53. Inactivation of this domain abolished DNA damage-dependent Rad53 phosphorylation, G2/M cell cycle phase arrest, and increase of RNR3 transcription but did not affect replication inhibition-dependent Rad53 phosphorylation. Thus, Rad53 integrates DNA damage signals by coupling with phosphorylated Rad9. The hitherto uncharacterized FHA domain appears to be a modular protein-binding domain.

  • Hofmann K, Bucher P
  • The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors.
  • Trends Biochem Sci. 1995; 20: 347-9
• Disease (disease genes where sequence variants are found in this domain)

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

  Protein	Disease
  Serine/threonine-protein kinase Chk2 (O96017) (SMART)	OMIM:604373: Li-Fraumeni syndrome OMIM:151623:

• 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 17.14 map04110 Cell cycle 17.14 map04115 p53 signaling pathway 11.43 map00230 Purine metabolism 8.57 map04520 Adherens junction 8.57 map04530 Tight junction 8.57 map04670 Leukocyte transendothelial migration 4.29 map04111 Cell cycle - yeast 4.29 map00380 Tryptophan metabolism 4.29 map00550 Peptidoglycan biosynthesis 2.86 map00562 Inositol phosphate metabolism 2.86 map03090 Type II secretion system 2.86 map00632 Benzoate degradation via CoA ligation 1.43 map00790 Folate biosynthesis 1.43 map03070 Type III secretion system 1.43 map00500 Starch and sucrose metabolism 1.43 map00906 Carotenoid biosynthesis - General 1.43 map04914 Progesterone-mediated oocyte maturation 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 FHA domain which could be assigned to a KEGG orthologous group, and not all proteins containing FHA 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 FHA domains in PDB

  PDB code	Main view	Title
  1dmz		A refined nmr structure of a new phophopeptide-binding domain containing the fha2 of rad53
  1fhq		Refined solution structure of the fha2 domain of rad53
  1fhr		Solution structure of the fha2 domain of rad53 complexed with a phosphotyrosyl peptide
  1g3g		Nmr structure of the fha1 domain of yeast rad53
  1g6g		X-ray structure of the n-terminal fha domain from s. cerevisiae rad53p in complex with a phosphothreonine peptide at 1.6 a resolution
  1gxc		Fha domain from human chk2 kinase in complex with a synthetic phosphopeptide
  1j4k		Solution structure of the fha2 domain of rad53 complexed with a phosphotyrosyl peptide derived from rad9
  1j4l		Solution structure of the fha2 domain of rad53 complexed with a phosphothreonyl peptide derived from rad9
  1j4o		Refined nmr structure of the fha1 domain of yeast rad53
  1j4p		Nmr structure of the fha1 domain of rad53 in complex with a rad9-derived phosphothreonine (at t155) peptide
  1j4q		Nmr structure of the fha1 domain of rad53 in complex with a rad9-derived phosphothreonine (at t192) peptide
  1k2m		Solution structure of the fha2 domain of rad53 complexed with a phosphotyrosyl peptide derived from rad9
  1k2n		Solution structure of the fha2 domain of rad53 complexed with a phosphothreonyl peptide derived from rad9
  1k3j		Refined nmr structure of the fha1 domain of yeast rad53
  1k3n		Nmr structure of the fha1 domain of rad53 in complex with a rad9-derived phosphothreonine (at t155) peptide
  1k3q		Nmr structure of the fha1 domain of rad53 in complex with a rad9-derived phosphothreonine (at t192) peptide
  1lgp		Crystal structure of the fha domain of the chfr mitotic checkpoint protein complexed with tungstate
  1lgq		Crystal structure of the fha domain of the chfr mitotic checkpoint protein
  1mzk		Nmr structure of kinase-interacting fha domain of kinase associated protein phosphatase, kapp in arabidopsis
  1qu5		Nmr structure of a new phosphotyrosine binding domain containing the fha2 domain of rad 53
  1r21		Solution structure of human ki67 fha domain
  1uht		Solution structure of the fha domain of arabidopsis thaliana hypothetical protein
  1wln		Solution structure of the fha domain of mouse afadin 6
  2a0t		Nmr structure of the fha1 domain of rad53 in complex with a biological relevant phosphopeptide derived from madt1
  2aff		The solution structure of the ki67fha/hnifk(226-269)3p complex
  2csw		Solution structure of the fha domain of human ubiquitin ligase protein rnf8
  2eh0		Solution structure of the fha domain from human kinesin- like protein kif1b
  2fez		Mycobacterium tuberculosis embr
  2ff4		Mycobacterium tuberculosis embr in complex with low affinity phosphopeptide
  2g1l		Crystal structure of the fha domain of human kinesin family member c
  2jkd		Structure of the yeast pml1 splicing factor and its integration into the res complex
  2jpe		Fha domain of nipp1
  2jqi		Nmr structure of the rad53 fha1 domain in complex with a phosphothreonien peptide derived from rad53 scd1
  2jqj		Nmr structure of yeast dun1 fha domain
  2jql		Nmr structure of the yeast dun1 fha domain in complex with a doubly phosphorylated (pt) peptide derived from rad53 scd1
  2kb3		Nmr structure of the phosphorylated form of odhi, podhi.
  2kb4		Nmr structure of the unphosphorylated form of odhi, odhi.
  2kfu		Pknb-phosphorylated rv1827
  2kkl		Solution nmr structure of fha domain of mb1858 from mycobacterium bovis. northeast structural genomics consortium target mbr243c (24-155).
  2pie		Crystal structure of the fha domain of rnf8 in complex with its optimal phosphopeptide
  3els		Crystal structure of yeast pml1p, residues 51-204
  3elv		Crystal structure of full-length yeast pml1p
  3fm8		Crystal structure of full length centaurin alpha-1 bound with the fha domain of kif13b (capri target)
  3gqs		Crystal structure of the fha domain of ct664 protein from chlamydia trachomatis
  3hue		Structure of the s. pombe nbs1 fha-brct1-brct2 domains
  3huf		Structure of the s. pombe nbs1-ctp1 complex
  3hx1		Crystal structure of the slr1951 protein from synechocystis sp. northeast structural genomics consortium target sgr167a
  3i0m		Structure of the s. pombe nbs1 fha/brct-repeat domain
  3i0n		Structure of the s. pombe nbs1 fha/brct-repeat domain
  3i6u		Structure and activation mechanism of the chk2 dna-damage checkpoint kinase
  3i6w		Structure and activation mechanism of the chk2 dna-damage checkpoint kinase

• Links (links to other resources describing this domain)

• PFAM	FHA
  INTERPRO	IPR000253
  PROSITE	FHA_DOMAIN

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