FHA Family from Maize

Required domains for FHA family:PF00498

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Forkhead Associated (FHA) domain proteins are present in transcription factors and signalling molecules like Kinase Associated Protein Phosphatases (KAPP), kinases, kinesins, RNA binding proteins and metabolic enzymes in organisms like yeast, bacteria, plants and animals. FHA domain is characterized by presence of 55-75 amino acid residues and only three invariant positions in the central domain including histidine, therefore implying its functionally important role (Hofmann and Bucher., 1995, Durocher and Jackson., 2002). Most FHA domains localize to the nucleus, therefore playing a role in DNA repair, transcription and cell cycle progression (Durocher and Jackson., 2002). In contrast to most FHA domains, Arabidopsis FHA domain containing KAPP does not localize to the nucleus and is associated with plasma membrane as a transmembrane component (Stone et al., 1994, Hofmann and Bucher., 1995). FHA domain is a modular phosphopeptide specific protein-protein interaction motif that binds partners phosphorylated on threonine or serine (Durocher et al., 1999, Durocher and Jackson., 2002). Arabidopsis genome consists of 18 genes encoding predicted FHA domain containing proteins, among which KAPP, FHA2, FHA3, PS1 (Parallel Spindle), DDL (Dawdle), NBS1 (Nijmegen Breakage Syndrome 1), TDP1 (Tyrosyl-DNA Phosphodiesterase 1) and ABA1 (Abscisic Acid Insensitive Mutant 1) have been studied. The Zea mays, Oryza sativa and Sorghum bicolor genomes consist of 31, 20 and 26 FHA genes respectively (Qiuling Wang., 2023).  

Arabidopsis, a KAPP protein containing FHA domain, interacts with some receptor-like kinases (RLK), thus regulating plant growth and pathogen response signaling pathways. ddl, T-DNA insertion mutant in Arabidopsis FHA domain containing gene DDL was so named because of its developmentally delayed growth period due defective vegetative and reproductive organs and reduced seed set. DDL encodes 314 amino acid residue proteins with putative nuclear localization signal (NLS) at arginine rich N- terminus and FHA domain at the C-terminus (Morris et al., 2006). DAWDLE not only plays a role in multiple aspects of early plant development but is also involved in miRNas and siRNAs biogenesis by interacting with dicer-like 1 (DCL1)  and recruiting DCL1 to its substrates,  since ddl mutants exhibited reduced levels of pri-mRNAs and mature mRNAs (Yu et al., 2008). DDL FHA domain binds to DCL1 through a conserved phospho-threonine recognition cleft, thus resulting in FHA domain mediated protein-protein interaction in plant miRNA processing (Machida and Yuan., 2013). FHA2 is a light stabilized suppressor of miRNA biogenesis, since based on biochemical assay it forms a complex with core microprocessors DCL1, HY1 (Hyponastic leaves) and SE (Serrate) to inhibit their pri-miRNA processing activity. fha2 mutant showed accumulation of miRNAs and reduction in pri-miRNAs and pri-miRNAs target genes. Thus FHA2 plays a role in miRNA biogenesis by regulating the activity of DCL1 and HY1 during de-etiolation since it is unstable in dark and stabilized by light during de-etiolation (Park et al., 2021). Arabidopsis, FHA2 domain forms a complex with ISWI (Imitation Switch) chromatin remodeler by interacting both in vivo and in vitro with RLT1 (Ringlet 1) and RLT2 redundant subunit of ISWI complex and thus regulates stamen development and plant fertility. The fha2 and rlt1/2 mutant showed shortened stamen filament resulting in reduced fertility (Gu et al., 2020). Arabidopsis FHA2 (Forkhead Associated Domain 2) domain plays a role in plant reproductive stage development mainly by regulating stamen development. Fha2 null mutant showed normal vegetative growth and fertile female flowers but reduced stamen number and defective stamen filament elongation along with increased ploidy in cotyledons and leaves (Ahn et al., 2012). From Arabidopsis protein microarray along with in vitro PARylation (Protein Poly(ADP-ribosyl)ation) assay, 54 putative substrates were identified as targets of PARP2 (poly (ADP-ribose) polymerase 2) among which one was DDL, which positively regulates both adapted and non-adapted pathogen stress response. PARP2 interacts with DDL and PARylates it. The PARylated DDL plays a role in plant immunity, since its levels were increased on bacterial flagellin treatment and the susceptibility to bacterial pathogens were decreased in ddl mutants (Feng et al., 2016). Peroxisomes are ubiquitous eukaryotic organelles that are involved in varied functions. Arabidopsis FHA3 domain negatively regulates peroxisome division by binding to the promoter region of peroxisome division factor gene PEX11b which mediates peroxisome elongation/tubulation (Desai et al., 2017).

Last updated June 2023 by Ankita Abnave


Hofmann K, Bucher P. The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors. Trends Biochem Sci. 1995 Sep;20(9):347-9. doi: 10.1016/s0968-0004(00)89072-6. PMID: 7482699.

Durocher D, Jackson SP. The FHA domain. FEBS Lett. 2002 Feb 20;513(1):58-66. doi: 10.1016/s0014-5793(01)03294-x. PMID: 11911881.

Stone JM, Collinge MA, Smith RD, Horn MA, Walker JC. Interaction of a protein phosphatase with an Arabidopsis serine-threonine receptor kinase. Science. 1994 Nov 4;266(5186):793-5. doi: 10.1126/science.7973632. PMID: 7973632.

Durocher D, Henckel J, Fersht AR, Jackson SP. The FHA domain is a modular phosphopeptide recognition motif. Mol Cell. 1999 Sep;4(3):387-94. doi: 10.1016/s1097-2765(00)80340-8. PMID: 10518219.

Morris ER, Chevalier D, Walker JC. DAWDLE, a forkhead-associated domain gene, regulates multiple aspects of plant development. Plant Physiol. 2006 Jul;141(3):932-41. doi: 10.1104/pp.106.076893. Epub 2006 May 5. PMID: 16679419; PMCID: PMC1489914.

Yu B, Bi L, Zheng B, Ji L, Chevalier D, Agarwal M, Ramachandran V, Li W, Lagrange T, Walker JC, Chen X. The FHA domain proteins DAWDLE in Arabidopsis and SNIP1 in humans act in small RNA biogenesis. Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10073-8. doi: 10.1073/pnas.0804218105. Epub 2008 Jul 15. PMID: 18632581; PMCID: PMC2481372.

Machida S, Yuan YA. Crystal structure of Arabidopsis thaliana Dawdle forkhead-associated domain reveals a conserved phospho-threonine recognition cleft for dicer-like 1 binding. Mol Plant. 2013 Jul;6(4):1290-300. doi: 10.1093/mp/sst007. Epub 2013 Jan 11. PMID: 23313986.

Ahn ER, Cho HK, Pai HS. The forkhead-associated domain 2 (FHA2) in Arabidopsis plays a role in plant fertility by regulating stamen development. Planta. 2013 Apr;237(4):1015-23. doi: 10.1007/s00425-012-1815-7. Epub 2012 Nov 30. PMID: 23192389.

Feng B, Ma S, Chen S, Zhu N, Zhang S, Yu B, Yu Y, Le B, Chen X, Dinesh-Kumar SP, Shan L, He P. PARylation of the forkhead-associated domain protein DAWDLE regulates plant immunity. EMBO Rep. 2016 Dec;17(12):1799-1813. doi: 10.15252/embr.201642486. Epub 2016 Oct 18. PMID: 27797852; PMCID: PMC5283580.

Wang Q. The role of forkhead-associated (FHA)-domain proteins in plant biology. Plant Mol Biol. 2023 Apr;111(6):455-472. doi: 10.1007/s11103-023-01338-4. Epub 2023 Feb 28. PMID: 36849846.

Desai M, Pan R, Hu J. Arabidopsis Forkhead-Associated Domain Protein 3 negatively regulates peroxisome division. J Integr Plant Biol. 2017 Jul;59(7):454-458. doi: 10.1111/jipb.12542. Epub 2017 Jun 6. PMID: 28332291.

Gu BW, Tan LM, Zhang CJ, Hou XM, Cai XW, Chen S, He XJ. FHA2 is a plant-specific ISWI subunit responsible for stamen development and plant fertility. J Integr Plant Biol. 2020 Nov;62(11):1703-1716. doi: 10.1111/jipb.12945. Epub 2020 Jun 15. PMID: 32396248.

Park SJ, Choi SW, Kim GM, Møller C, Pai HS, Yang SW. Light-stabilized FHA2 suppresses miRNA biogenesis through interactions with DCL1 and HYL1. Mol Plant. 2021 Apr 5;14(4):647-663. doi: 10.1016/j.molp.2021.01.020. Epub 2021 Jan 29. PMID: 33524550.




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