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InterPro: IPR008984 SMAD/FHA domain
Protein matches
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UniProtKB Matches: 5596 proteins |
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Accession
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IPR008984 SMAD_FHA_domain |
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Type
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Domain |
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Signatures
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InterPro Relationships
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Children
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IPR000253 Forkhead-associated
IPR017855 SMAD domain-like
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Found in
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IPR006518 Trypanosome RHS
IPR006550 Polynucleotide kinase 3-phosphatase
IPR012843 Type III secretion system YscD/HrpQ
IPR016256 Serine/threonine-protein kinase RAD53
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InterPro annotation
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 Entry Details in BioMart
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Abstract
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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) homolog) 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.
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Structural links
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Interactions
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This domain has been experimentally proven to be involved in Protein:Protein interactions. Representative
data is shown with the following
example proteins:
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Publications
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1.
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Durocher D, Taylor IA, Sarbassova D, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB.
The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.
Mol. Cell 6 1169-82 2000
[PubMed: 11106755]
http://dx.doi.org/10.1016/S1097-2765(00)00114-3
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2.
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Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP, Jeffrey PD.
Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate.
Structure 10 891-9 2002
[PubMed: 12121644]
http://dx.doi.org/10.1016/S0969-2126(02)00776-1
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3.
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Li J, Williams BL, Haire LF, Goldberg M, Wilker E, Durocher D, Yaffe MB, Jackson SP, Smerdon SJ.
Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2.
Mol. Cell 9 1045-54 2002
[PubMed: 12049740]
http://dx.doi.org/10.1016/S1097-2765(02)00527-0
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4.
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Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massague J, Shi Y.
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 2001
[PubMed: 11779503]
http://dx.doi.org/10.1016/S1097-2765(01)00421-X
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5.
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Shi Y, Hata A, Lo RS, Massague J, Pavletich NP.
A structural basis for mutational inactivation of the tumour suppressor Smad4.
Nature 388 87-93 1997
[PubMed: 9214508]
http://dx.doi.org/10.1038/40431
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6.
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Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S.
Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads.
EMBO J. 20 4132-42 2001
[PubMed: 11483516]
http://dx.doi.org/10.1093/emboj/20.15.4132
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7.
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Qin BY, Liu C, Lam SS, Srinath H, Delston R, Correia JJ, Derynck R, Lin K.
Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.
Nat. Struct. Biol. 10 913-21 2003
[PubMed: 14555996]
http://dx.doi.org/10.1038/nsb1002
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Additional Reading
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Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J.
RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.
Cell 131 2007 901-14
[PubMed: 18001825]
http://dx.doi.org/10.1016/j.cell.2007.09.041
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Iles N, Rulten S, El-Khamisy SF, Caldecott KW.
APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks.
Mol. Cell. Biol. 27 2007 3793-803
[PubMed: 17353262]
http://dx.doi.org/10.1128/MCB.02269-06
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Lee H, Yuan C, Hammet A, Mahajan A, Chen ES, Wu MR, Su MI, Heierhorst J, Tsai MD.
Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade.
Mol. Cell 30 2008 767-78
[PubMed: 18570878]
http://dx.doi.org/10.1016/j.molcel.2008.05.013
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Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabasi AL, Vidal M, Zoghbi HY.
A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.
Cell 125 2006 801-14
[PubMed: 16713569]
http://dx.doi.org/10.1016/j.cell.2006.03.032
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Alderwick LJ, Molle V, Kremer L, Cozzone AJ, Dafforn TR, Besra GS, Futterer K.
Molecular structure of EmbR, a response element of Ser/Thr kinase signaling in Mycobacterium tuberculosis.
Proc. Natl. Acad. Sci. U.S.A. 103 2006 2558-63
[PubMed: 16477027]
http://dx.doi.org/10.1073/pnas.0507766103
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Ali AA, Jukes RM, Pearl LH, Oliver AW.
Specific recognition of a multiply phosphorylated motif in the DNA repair scaffold XRCC1 by the FHA domain of human PNK.
Nucleic Acids Res. 37 2009 1701-12
[PubMed: 19155274]
http://dx.doi.org/10.1093/nar/gkn1086
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Bernstein NK, Williams RS, Rakovszky ML, Cui D, Green R, Karimi-Busheri F, Mani RS, Galicia S, Koch CA, Cass CE, Durocher D, Weinfeld M, Glover JN.
The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase.
Mol. Cell 17 2005 657-70
[PubMed: 15749016]
http://dx.doi.org/10.1016/j.molcel.2005.02.012
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