InterPro domain: IPR008984

FHA and SMAD (MH2) domains share a common structure consisting of a sandwich of eleven beta strands in two sheets with Greek key topology. Forkhead-associated (FHA) domains were originally identified as a sequence profile of about 75 amino acids, whereas the full-length domain is closer to about 150 amino acids. FHA domains are found in transcription factors, kinesin motors, and in a variety of other signalling molecules in organisms ranging from eubacteria to humans. FHA domains are protein-protein interaction domains that are specific for phosphoproteins. FHA-containing proteins function in maintaining cell-cycle checkpoints, DNA repair and transcriptional regulation. FHA domain proteins include the Chk2/Rad53/Cds1 family of proteins that contain one or more FHA domains, as well as a Ser/Thr kinase domain [ 1 , 2 , 3 ].

SMAD (Mothers against decapentaplegic (MAD) homologue) domain proteins are found in a range of species from nematodes to humans. These highly conserved proteins contain an N-terminal MH1 domain that contacts DNA, and is separated by a short linker region from the C-terminal MH2 domain, the later showing a striking similarity to FHA domains. SMAD proteins mediate signalling by the TGF-beta/activin/BMP-2/4 cytokines from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins fall into three functional classes: the receptor-regulated SMADs (R-SMADs), including SMAD1, -2, -3, -5, and -8, each of which is involved in a ligand-specific signalling pathway [ 4 ]; the comediator SMADs (co-SMADs), including SMAD4, which interact with R-SMADs to participate in signalling [ 5 ]; and the inhibitory SMADs (I-SMADs), including SMAD6 and -7, which block the activation of R-SMADs and Co-SMADs, thereby negatively regulating signalling pathways [ 6 ].

Domains with this fold are also found as the transactivation domain of interferon regulatory factor 3 (IRF3), which has a weak homology to SMAD domains [ 7 ], and the N-terminal domain of EssC protein in Staphylococcus aureus.

1. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol. Cell 6, 1169-82
2. Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate. Structure 10, 891-9
3. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol. Cell 9, 1045-54
4. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol. Cell 8, 1277-89
5. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388, 87-93
6. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J. 20, 4132-42
7. Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation. Nat. Struct. Biol. 10, 913-21