 Abstract
The forkhead-associated FHA domain is a phosphopeptide-binding domain first identified in a group of forkhead transcription factors (Hofmann and Bucher, 1995). FHA are small domains (<100 aminoacids) which form a sandwich of two antiparallel beta sheets (Walker et al., 2000). They are present in a wide variety of proteins from both prokaryotes and eukaryotes (Walker et al., 2000). The existence of FHA domains in a wide variety of proteins means they are involved in diverse cellular functions including signal transduction and vesicular transport. In plants, FHA domains participate in the regulation of receptor-like protein kinase signalling pathways (Doren et al., 2003). There are many nuclear FHA-domain containing proteins: these have a variety of roles involved in cell-cycle checkpoint control, DNA repair, signal transduction, transcriptional regulation, and pre-mRNA splicing. Some of the FHA domain containing proteins are present in the plasma membrane. While FHAs bind to phosphothreonine motifs, BRCT domains recognize phosphoserine motifs in otherwise similar nuclear regulatory contexts. Although weak in vitro binding of phosphoserine and phosphotyrosine peptides has been observed, all high affinity interactions utilize phosphothreonine, which may be an essential requirement for the biological ligands. The optimal FHA domain binding sequence is a phosphothreonine peptide with pT+3 specificity (Li et al., 2003). So far there are two well characterised motifs TXX[ILV] and TXX[DE] – while TXXC and TXXA have been observed, they are not currently modelled in ELM. The TXXC linear motif forms part of a larger induced fit interaction with the FHA domain (Byeon et al.,2004). More variations among the FHA-binding motifs are expected to be found.
Selected references
| Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M | | NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a
regulator of pre-mRNA splicing and mitotic entry. | | J Biol Chem 2000 Aug 18;275(33) : 25411-7. | | PMID: 10827081 |
| Braun DM, Stone JM, Walker JC | | Interaction of the maize and Arabidopsis kinase interaction domains with a
subset of receptor-like protein kinases: implications for transmembrane
signaling in plants. | | Plant J 1997 Jul;12(1) : 83-95. | | PMID: 9263453 |
| Byeon IJ, Yongkiettrakul S, Tsai MD | | Solution structure of the yeast Rad53 FHA2 complexed with a
phosphothreonine peptide pTXXL: comparison with the structures of
FHA2-pYXL and FHA1-pTXXD complexes. | | J Mol Biol 2001 Nov 30;314(3) : 577-88. | | PMID: 11846568 |
| Lee GI, Ding Z, Walker JC, Van Doren SR | | NMR structure of the forkhead-associated domain from the Arabidopsis
receptor kinase-associated protein phosphatase. | | Proc Natl Acad Sci U S A 2003 Sep 30;100(20) : 11261-6. | | PMID: 14500786 |
| Pike BL, Yongkiettrakul S, Tsai MD, Heierhorst J | | Mdt1, a novel Rad53 FHA1 domain-interacting protein, modulates DNA damage
tolerance and G(2)/M cell cycle progression in Saccharomyces cerevisiae. | | Mol Cell Biol 2004 Apr;24(7) : 2779-88. | | PMID: 15024067 |
| Sueishi M, Takagi M, Yoneda Y | | The forkhead-associated domain of Ki-67 antigen interacts with the novel
kinesin-like protein Hklp2. | | J Biol Chem 2000 Sep 15;275(37) : 28888-92. | | PMID: 10878014 |
| Sun Z, Hsiao J, Fay DS, Stern DF | | Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage
checkpoint. | | Science 1998 Jul 10;281(5374) : 272-4. | | PMID: 9657725 |
| Williams RW, Wilson JM, Meyerowitz EM | | A possible role for kinase-associated protein phosphatase in the
Arabidopsis CLAVATA1 signaling pathway. | | Proc Natl Acad Sci U S A 1997 Sep 16;94(19) : 10467-72. | | PMID: 9294234 |
| Yongkiettrakul S, Byeon IJ, Tsai MD | | The ligand specificity of yeast Rad53 FHA domains at the +3 position is
determined by nonconserved residues. | | Biochemistry 2004 Apr 6;43(13) : 3862-9. | | PMID: 15049693 |
| Zhou Z, Elledge SJ | | DUN1 encodes a protein kinase that controls the DNA damage response in
yeast. | | Cell 1993 Dec 17;75(6) : 1119-27. | | PMID: 8261511 |
This ELM has been assigned the following Gene Ontology (GO) terms for biological process, cellular component and molecular function.
|
Biological Process |
|
|
DNA repair
|
|
|
cell cycle checkpoint
|
|
|
G2/M transition of mitotic cell cycle
|
|
|
Response to DNA damage stimulus
|
|
|
Cellular Component |
|
|
nucleus |
|
|
Molecular Function |
|
|
protein binding |
|
|
protein domain specific binding |
|
|
