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Function and evolution of ubiquitous bacterial signaling adapter phosphopeptide recognition domain FHA
Cellular Signalling 25 (2013) 660–665
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Review
Function and evolution of ubiquitous bacterial signaling adapter phosphopeptide recognition domain FHA Hong Weiling, Yu Xiaowen, Li Chunmei, Xie Jianping ⁎ Institute of Modern Biopharmaceuticals, State Key Laboratory breeding base of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Chongqing 400715, China
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Article history: Received 19 November 2012 Accepted 23 November 2012 Available online 29 November 2012 Keywords: FHA domain Phosphopeptide recognition Function Structure Evolution Distribution
a b s t r a c t Forkhead-associated domain (FHA) is a phosphopeptide recognition domain embedded in some regulatory proteins. With similar fold type to important eukaryotic signaling molecules such as Smad2 and IRF3, the role of bacterial FHA domain is intensively pursued. Reported bacterial FHA domain roles include: regulation of glutamate and lipids production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbohydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions. To provide basis for the studies of other bacterial FHA domain containing proteins, the status of bacterial FHA functionality and evolution were summarized. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction of FHA domain . . . . . . . . . . . . . . . . Evolution of FHA domain . . . . . . . . . . . . . . . . . . Structure of FHA domain . . . . . . . . . . . . . . . . . . Distribution of bacterial FHA domain . . . . . . . . . . . . Functionalities of FHA domain . . . . . . . . . . . . . . . 5.1. Regulation of glutamate production . . . . . . . . . 5.2. Increase of lipid level . . . . . . . . . . . . . . . . 5.3. Regulation of cell shape . . . . . . . . . . . . . . . 5.4. Type III secretion . . . . . . . . . . . . . . . . . . 5.5. Ethambutol resistance . . . . . . . . . . . . . . . . 5.6. Sporulation . . . . . . . . . . . . . . . . . . . . . 6. Regulation of FHA domain activity . . . . . . . . . . . . . 6.1. Phosphorylation activity of the FHA-containing protein 6.2. Phosphorylation inhibits the FHA-containing protein . 7. Analogs of FHA domain—MH2 . . . . . . . . . . . . . . . 8. Significance of FHA domain . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction of FHA domain FHA is phosphopeptide recognition domain present in some regulatory proteins, bearing ubiquitous phosphothreonine-dependent binding ⁎ Corresponding author. Tel./fax: +86 23 68367108. E-mail address: [email protected] (X. Jianping).
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module or phosphotyrosine-dependent binding module. The affinity of the former is higher than the latter [1]. Phosphopeptide recognition protein is a major player in signaling [2]. In eukaryotes, many FHA domain-containing proteins localize at the nucleus and function in the establishment of maintenance of cell cycle checkpoints, DNA repair, or transcriptional regulation [3]. FHA is a well known ubiquitous phosphothreonine-dependent binding module. However, their function
0898-6568/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cellsig.2012.11.019
H. Weiling et al. / Cellular Signalling 25 (2013) 660–665
in bacterial physiology and signaling remained largely obscure until 2002[4]. FHA-containing proteins are found widespread among bacteria, such as Myxococcus xanthus, Deinococcus radiodurans, Anabaena, Bacillus halodurans, Synechocystis, Streptomyces coelicolor, Pseudomonas aeruginosa, Agrobacterium tumefaciens, Sulfolobus acidocaldarius, and Sulfolobus tokodaii [5–10]. FHA domain roles in bacteria have been characterized: glutamate and lipid production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbohydrate storage and transport, pathogenic and symbiotic host–bacterium interactions [11–14]. This study aims to summarize FHA functionality and evolution. 2. Evolution of FHA domain The origin of FHA domain is intriguing. For intracellular parasites, the putative FHA-containing proteins might obtain genes encoding FHA-containing proteins from their eukaryotic hosts. However, FHA-containing proteins are also found in a other free-living bacteria, such as D. radiodurans, M. xanthus, Anabaena, Synechocystis, P. aeruginosa, B. halodurans, S. coelicolor and A. tumefaciens (http://pfam.sanger.ac.uk/ family/FHA). The presence of FHA domains in proteobacteria and cyanobacteria implicates that eukaryotic FHA domains might have evolved from nuclear-transferred genes of endosymbionts [15,16]. Whatever the origin of bacterial FHA domains is, the modular phosphopeptide recognition might undergo several times during evolution to meet its biological roles [17]. The ancient FHA domain module [18] might have been replaced by other phosphopeptide-binding module during evolution [19], as evidenced by the PinA protein of Dictyostelium discoideum, a peptidyl-prolyl isomerase of the Pin1 family [17]. Unlike its cognate eukaryotic phosphopeptide-binding domain, DdPinA lacks the phosphopeptide-binding WW domain in its N-terminus [17]. Fig. 1 is the phylogeny of FHA-containing bacteria.
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divergent spacer regions: GR, SXXH, and NG[1]. FHA domain contains 11-stranded beta sandwich, with small helical insertions at the loops connecting the strands [20]. The conserved blocks usually distributed as following: GR at the end of strand three, SXXH before strand five and NG before strand seven [17]. Fig. 2 is the characteristic structure of FHA domain. 4. Distribution of bacterial FHA domain The ubiquitous of FHA domains among bacteria does not necessarily mean there existence in all bacteria. However, three categories do have FHA domains, namely the mycobacteria, the cyanobacteria, some Gram-negative proteobacteria and the chlamydias [4]. Table 1 is the distribution of the bacterial FHA domain. 5. Functionalities of FHA domain FHA domain has been implicated in the glutamate and lipid production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbonhydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions. Fig. 3 is the schematic representation of the roles of bacterial FHA domains. 5.1. Regulation of glutamate production Corynebacterium glutamicum, a Gram-positive soil bacterium, is an industrial producer of multiple products [22]. Arabinose-inducible expression system regulated expression of C. glutamicum OdhI gene can change the yields of glutamate under biotin non-limiting conditions [23]. OdhI gene product contains FHA domain and is an inhibitor of alpha-oxoglutarate dehydrogenase [24]. 5.2. Increase of lipid level
3. Structure of FHA domain The representative FHA domain contains approximately 55–75 amino acids with three highly conserved blocks separated by some
Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis [25]. Rv0019c (fhaB, Forkhead-associated domain-containing protein), a putative virulence factor, is involved in regulating cell shape
Fig. 1. Phylogeny of FHA-containing bacteria. Phylogeny reveals the diversity of FHA-containing bacteria. FHA domains are found in a wide range of bacteria including bacillus, coccus and vibrio. Two FHA-containing proteins are similar in P. aeruginosa. The FHA-containing protein in A. tumefaciens and R. leguminosarum resembles each other. The lower similarity of FHA-containing protein in the same bacterium than those from two bacteria indicates that FHA domain is not a good taxonomy marker for bacteria.
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Fig. 2. Characteristic structure of FHA domain. Yellow indicates the identical sequences. Mtb is the abbreviation of Mycobacterium tuberculosis. EmbR, fhaB and GarA are the FHA containing protein in M. tuberculosis. Three highly conserved blocks: GR, SXXH, and NG. Blue arrow represents 11-stranded beta sandwich.
[26]. Rv0019c can interact with polyketide-associated protein PapA5, a putative membrane protein involved in the biosynthesis of virulence enhancing lipids [27,28]. Rv0019c FHA domain was reported to mediate the interaction with PapA5. This FHA domain was identified as novel phophoindependent binding surface [26].
interaction between the protein–phosphoprotein regulating the arabinan synthesis [42]. One possible scenario is that pknH phosphorylates embR, which is then activated through an FHA-mediated interaction [43]. Intriguingly, an ethambutol resistance mutation occurred at a residue within the EmbR FHA domain, indicating that modification of FHA-mediated interactions can cause an ethambutol-resistance [44].
5.3. Regulation of cell shape 5.6. Sporulation Clostridium acetobutylicum was tagged as the “Weizmann Organism”, and can produce acetone, ethanol, and butanol from starch simultaneously [29]. CAC0504 in rodA/pbp gene cluster is involved in the regulation of cell shape [30]. OdhI gene encodes an inhibitor of alphaoxoglutarate dehydrogenase. FtsZ is a wide distributed cytoskeletal protein involved in the archaeal and bacterial cell division. OdhI and FtsZ are substrates of PknA, PknB and PknL. This suggested that the OdhI might engage in the cell division [31].
M. xanthus, with a complex starvation-induced developmental program that cause starving bacteria self-organize to form fruiting bodies, is a model organism for development [45]. EspA is a histidine protein kinase with a FHA domain at the N-terminus [46]. EspA is part of a two-component signal transduction system that regulates the timing of sporulation. EspA mutants, encoding a deformed hybrid histidine kinase, change the timing of developmental program [46]. This shows that EspA plays a significant role in the sporulation [47].
5.4. Type III secretion 6. Regulation of FHA domain activity Chlamydia trachomatis is a Gram-negative bacteria [32], an obligate intracellular human pathogen leading to urethritis, proctitis, trachoma and infertility [33–35]. CT664 encodes a single FHA-domain-containing protein found in three chlamydial species. The gene encoding this protein situates within the type III secretion system cluster that also encodes an STPK (CT673 in C. trachomatis) [36], suggesting a role of CT664 in the chlamydial type III secretion system by mediating phosphorylationdependent protein–protein interactions [37,38]. 5.5. Ethambutol resistance EmbR (encoded by Rv1267) is adjacent to a cluster of ATP-binding cassette transporter genes and pknH [39,40]. Rv1267 contains carboxy-terminal FHA domain and is a transcriptional regulator of the embA and embB genes, which encode cell wall arabinosyl transferases related to ethambutol resistance [41]. This FHA domain mediates the
The serine/threonine protein kinases were widely recognized as eukaryote unique proteins [48] until the discovery of their occurrence in prokaryotes [49–52]. These protein kinases were assigned similar roles in signal transduction [53,54] as those “two-component systems” sensor histidine kinases [55,56]. 6.1. Phosphorylation activity of the FHA-containing protein M. tuberculosis Rv1747, a predicted ATP-binding cassette transporter essential for its in vivo growth, contains two FHA domains [57,58]. PknF can also phosphorylate Rv1747 on two specific threonine residues, namely Thr-150 and Thr-208 [21]. Other FHA-containing proteins are Rv0020c and the heat-shock protein GroEL1 [59,60]. Rv1747 mutation of threonine-to-alanine can alter infection outcome. This implicates that phosphorylation can alter
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Table 1 Distribution of the bacterial FHA domain. Protein (length)
Organism
FHA domain
Associated STPK/STPPs
Comments
fhaB (155)
Mycobacterium tuberculosis
57–149
STPK: pknA/pknB STPP: ppp STPK: pknA/pknB, STPP: ppp STPK: pknH
In rodA/pbp gene cluster; involved in regulating cell shape
fhaA (527)
389–525
Rv1267c (388)
257–380
Rv1747 (865)
177–299
STPK: pknE/pknF Thr-150 and Thr-208
Rv1827 (162) Rv3360 (122) OdhI (143) BH1777 (230) DRA0333 (314) CAC0036 (468)
35–156 4–92 49–138 18–102 167–311 379–468
STPK: pknG/pknB
CAC0039 (1544)
111–201
STPP: CAC0035
CAC0406 (516)
420–516
CAC0408 (1524)
82–190
STPP: CAC0407 STPK: CAC0404 STPP: CAC0407 STPK: CAC0404
CAC0504 (159) SCH69.13 (290)
Corynebacterium glutamicum Bacillus halodurans Deinococcus radiodurans Clostridium acetobutylicum
Streptomyces coelicolor
84–158 159–286
BH2504 STPK: DRA0332 STPP: CAC0035
STPK: SCH69.18 STPP: SCH69.15 STPK: SCH69.18 STPP: SCH69.15
SCH69.14 (172)
46–168
SC1A8A.04c (267) SCE50.03 (1345)
141–260 94–201
SCBAC1A6.03 (183) SC6D10.12 (604)
102–179 452–594
Two STPKs
SCI33.05c (876)
1–89, 201–307
STPP
25–107
STPP: stp1 STPK: stk1 STPP: PA0075, STPK: ppkA STPP: impM STPK: impN STPP: AGR_L_1064, TPK: AGR_L_1065 STPP: mlr2361, STPK: mlr2363 No STPK in genome No STPK in genome STPK: pkn3
PA1665 (397)
Pseudomonas aeruginosa PAO1
PA0081 (497)
23–121 15–113
AGR_L_1057 (399)
Rhizobium leguminosarum bv. trifolii Agrobacterium tumefaciens
mlr2345 (486) Ecs0229 (616) vca0112 (495) orf1 (833)
Mesorhizobium loti Escherichia coli O157 Vibrio cholerae Myxococcus xanthus
13–106
ImpI (399)
EspA (388) CT664 (768) YscD (829)
Chlamydia trachomatis Yersinia enterocolitica
28–113
18–120 8–108 136–279, 271–385 32–148 355–476
STPK: pkaA/pkaB
STPK: CT673
the activity of Rv1747, thereby effecting the growth of M. tuberculosis [21].
6.2. Phosphorylation inhibits the FHA-containing protein Unphosphorylated FHA-domain protein GarA regulates primary metabolism, while phosphorylated one can mediate the GarA autoinhibition [61]. Solution structures of the unphosphorylated and phosphorylated demonstrated major conformational difference between the two forms [10]. GarA can bind its own phosphorylated N-terminal of the FHA domain to self-inhibit [61]. This represents a new autoinhibition mechanism in FHA domain protein [62].
In rodA/pbp gene cluster; involved in regulating cell shape EmbR; contains an amino-terminal BAD domain; regulates cell wall arabinosyltransferases; involved in ethambutol resistance; adjacent cluster of ABC transporter genes ABC transporter that is necessary for growth of M. tuberculosis in vivo and contains two Forkhead-associated (FHA) domains[21]. GarA; implicated in regulation of glycogen storage No functional assignment Contains carboxy-terminal DNA-binding domain Contains Ala/Pro-rich low-complexity sequence Contains TM domain; clusters with WXG100 and acetobutylicum tetratricopeptide repeat genes Contains TM domain and three SpoIIIE/FtsK domains; clusters with WXG100 and tetratricopeptide repeat genes Contains TM domain; clusters with WXG100 and etratricopeptide repeat genes Contains TM domain and three SpoIIIE/FtsK domains; clusters with WXG100 and tetratricopeptide repeat genes In rodA/pbp gene cluster; involved in regulating cell shape? Orthologue of Rv0020c Orthologue of Rv0019c Orthologue of GarA Contains proline-rich low-complexity sequence; contains FtsK/SpoIIIE domain; adjacent cluster of ABC transporter genes Clusters with amylase genes; involved in glycogen metabolism? Contains low-complexity proline-rich sequence; in sugar transport system operon; regulates uptake of unidentified carbohydrate? Contains two amino-terminal FHA domains flanking proline-rich low-complexity sequence, followed by an ABC-transporter domain and TM domains In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster; in O-island In impA-N-like gene cluster Contains a proline-rich amino-terminal domain followed by two FHA domains Histidine-kinase; a complex domain architecture; regulates the timing of sporulation In type III secretion gene cluster, see below Amino-terminal putative FHA domain also evident in some other SctD proteins, e.g. PscD from Pseudomonas aeruginosa, HrpQ from Erwinia amylovora
7. Analogs of FHA domain—MH2 Intriguingly, the fold of the FHA domain is extremely similar to the bend of the Smad MH2 domain [63–65]. The MH2 domain of Smad transcriptional regulators plays a crucial role in Smad-dependent TGFL signaling and serves as a binding interface for the tetra-phosphorylated type I TGFL receptor (TLR-I) [66]. The conserved fold might demonstrate functional conservation [67]. Mapping of the interaction determinants on the MH2 domain suggested that the region required for the interaction of MH2 is similar to the phosphopeptide interaction region of FHA domains [67–69]. This striking similarity leads to the possibility that the FHA and MH2 domains might share a common ancestor which has a phosphopeptide-binding activity [67].
664
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Fig. 3. Schematic representation of the roles of bacterial FHA domains. (A) Schematic representation of bacterial FHA domain roles: Glutamate production, lipids increased, regulation of cell shape, type III secretion, ethambutol resistance, and sporulation are well documented roles of FHA domain. EspA: putative histidine protein kinase; FruA: putative response regulator that governs a branched signaling pathway inside cells; OdhA: alpha-oxoglutarate dehydrogenase A; OdhI: alpha-oxoglutarate dehydrogenase I; PknG: Serine/threonine-protein kinase G; PknB: Serine/threonine-protein kinase B; Pap5: polyketide-associated Protein 5; fhaB: Forkhead-associated domain B; PDIM: phthiodiolone dimycocerosate esters; YscD: Yop secretion D; syc: cytoplasmic chaperones; (B) and (C):locations of FHA domains in FHA-containing protein. Trans-reg-C: Transcriptional regulatory protein, C terminal; DUF1706: Protein of unknown function. This family contains many hypothetical proteins from bacteria and yeast; PAS: putative active site domain; Response-reg: Response regulator receiver domain; MARCKS: MARCKS family; Type-III-yscD: type III secretion apparatus protein, YscD/HrpQ family; ABCG-EPDR: Eye pigment and drug resistance transporter subfamily G of the ATP-binding cassette superfamily; ABC2-membrane: ABC-2 type transporter; SalX: ABC-type antimicrobial peptide transport system, ATPase component.
IRF-3, a member of the interferon regulatory factor (IRF) family, plays an important role in the development of the IFN antiviral response [70,71]. IRF-3 shares a marked structural similarity to the MH2 domain and the FHA domain, indicating a common molecular mechanism of action among these domains of signaling mediators [63].
[11–14]. The structural continuum of phosphopeptide recognition modules provides a basis for incremental phosphopeptide activity inhibition [78–80]. Therapeutic inhibitors of FHA domains active in bacteria might be promising novel antibiotics and tool compounds to dissect FHA-dependent processes in vivo.
8. Significance of FHA domain Acknowledgments SH2 domain inhibitors such as 1,4-cis-enediol scaffold, 1,2dihydroxybenzene, G7-18NATE cyclic peptide, and specific FN3 monobody might be good medications against various pathogens [72–77]. With the recent progress in effective anti-SH2 compounds [47,48], intensive studies are directed to identify similar anti-FHA molecules capable of blocking signal-dependent protein–protein interactions. Bacterial FHA domain are involved in glutamate production, lipid accumulation, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbonhydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions
This work was funded by the National Natural Science Foundation (Grant No. 81071316 and No.81271882), National Megaprojects for Key Infectious Diseases (No.2008ZX10003-006), New Century Excellent Talents in Universities (NCET-11-0703), Excellent PhD Thesis Fellowship of Southwest University (Grant Nos. kb2009010 and ky2011003), the Fundamental Research Funds for the Central Universities) Grant No. XDJK2012D011, XDJK2011C020, XDJK2013D003 and XDJK2012D007), and Natural Science Foundation Project of CQ CSTC (Grant No. CSTC, 2010BB5002).
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References [1] K. Hofmann, P. Bucher, Trends in Biochemical Sciences 20 (1995) 347–349. [2] S. Richter, V. Bouvet, M. Wuest, R. Bergmann, J. Steinbach, J. Pietzsch, I. Neundorf, F. Wuest, Nuclear Medicine and Biology 39 (2012) 1202–1212. [3] D. Durocher, I.A. Taylor, D. Sarbassova, L.F. Haire, S.L. Westcott, S.P. Jackson, S.J. Smerdon, M.B. Yaffe, Molecular Cell 6 (2000) 1169–1182. [4] M. Pallen, R. Chaudhuri, A. Khan, Trends in Microbiology 10 (2002) 556–563. [5] L. Jelsbak, M. Givskov, D. Kaiser, Proceedings of the National Academy of Sciences of the United States of America 102 (2005) 3010–3015. [6] G. Jones, R. Del Sol, E. Dudley, P. Dyson, Microbial Biotechnology 4 (2011) 263–274. [7] F. Hsu, S. Schwarz, J.D. Mougous, Molecular Microbiology 72 (2009) 1111–1125. [8] J.D. Mougous, C.A. Gifford, T.L. Ramsdell, J.J. Mekalanos, Nature Cell Biology 9 (2007) 797–803. [9] J. Reimann, K. Lassak, S. Khadouma, T.J. Ettema, N. Yang, A.J. Driessen, A. Klingl, S.V. Albers, Molecular Microbiology 86 (2012) 24–36. [10] X. Duan, Z.G. He, Biochemical and Biophysical Research Communications 407 (2011) 242–247. [11] D.L. Johnson, J.B. Mahony, Journal of Bacteriology 189 (2007) 7549–7555. [12] M.D. Tsai, Structure 10 (2002) 887–888. [13] M.A. McDowell, S. Johnson, J.E. Deane, M. Cheung, A.D. Roehrich, A.J. Blocker, J.M. McDonnell, S.M. Lea, The Journal of Biological Chemistry 286 (2011) 30606–30614. [14] J.A. Ross, G.V. Plano, Journal of Bacteriology 193 (2011) 2276–2289. [15] V.V. Emelyanov, FEBS Letters 501 (2001) 11–18. [16] J. Falck, C. Lukas, M. Protopopova, J. Lukas, G. Selivanova, J. Bartek, Oncogene 20 (2001) 5503–5510. [17] D. Durocher, S.P. Jackson, FEBS Letters 513 (2002) 58–66. [18] B. Wang, S. Yang, L. Zhang, Z.G. He, Journal of Bacteriology 192 (2010) 1956–1964. [19] R.A. Cigliano, W. Sanseverino, G. Cremona, F.M. Consiglio, C. Conicella, BMC Evolutionary Biology 11 (2011) 78. [20] H. Liao, I.J. Byeon, M.D. Tsai, Journal of Molecular Biology 294 (1999) 1041–1049. [21] V.L. Spivey, V. Molle, R.H. Whalan, A. Rodgers, J. Leiba, L. Stach, K.B. Walker, S.J. Smerdon, R.S. Buxton, The Journal of Biological Chemistry 286 (2011) 26198–26209. [22] M.D. Collins, L. Hoyles, G. Foster, E. Falsen, International Journal of Systematic and Evolutionary Microbiology 54 (2004) 925–928. [23] Y. Zhang, X. Shang, S. Lai, G. Zhang, Y. Liang, T. Wen, Applied and Environmental Microbiology (2012). [24] A. Niebisch, A. Kabus, C. Schultz, B. Weil, M. Bott, The Journal of Biological Chemistry 281 (2006) 12300–12307. [25] P. Sudre, G. ten Dam, A. Kochi, Bulletin of the World Health Organization 70 (1992) 149–159. [26] M. Gupta, A. Sajid, G. Arora, V. Tandon, Y. Singh, The Journal of Biological Chemistry 284 (2009) 34723–34734. [27] O.A. Trivedi, P. Arora, A. Vats, M.Z. Ansari, R. Tickoo, V. Sridharan, D. Mohanty, R.S. Gokhale, Molecular Cell 17 (2005) 631–643. [28] K.C. Onwueme, J.A. Ferreras, J. Buglino, C.D. Lima, L.E. Quadri, Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 4608–4613. [29] L.K. Bowles, W.L. Ellefson, Applied and Environmental Microbiology 50 (1985) 1165–1170. [30] R. Chaba, M. Raje, P.K. Chakraborti, European journal of biochemistry/FEBS 269 (2002) 1078–1085. [31] C. Schultz, A. Niebisch, A. Schwaiger, U. Viets, S. Metzger, M. Bramkamp, M. Bott, Molecular Microbiology 74 (2009) 724–741. [32] C. Benson, J. Segreti, H. Kessler, D. Hines, L. Goodman, R. Kaplan, G. Trenholme, European Journal of Clinical Microbiology 6 (1987) 173–178. [33] A. Balakrishnan, B. Patel, S.A. Sieber, D. Chen, N. Pachikara, G. Zhong, B.F. Cravatt, H. Fan, The Journal of Biological Chemistry 281 (2006) 16691–16699. [34] T.C. Quinn, S.E. Goodell, E. Mkrtichian, M.D. Schuffler, S.P. Wang, W.E. Stamm, K.K. Holmes, The New England Journal of Medicine 305 (1981) 195–200. [35] J. Henry-Suchet, F. Catalan, V. Loffredo, D. Serfaty, A. Siboulet, Y. Perol, M.J. Sanson, C. Debache, F. Pigeau, R. Coppin, J. de Brux, T. Poynard, American Journal of Obstetrics and Gynecology 138 (1980) 1022–1025. [36] E. Lorenzini, A. Singer, B. Singh, R. Lam, T. Skarina, N.Y. Chirgadze, A. Savchenko, R.S. Gupta, Journal of Bacteriology 192 (2010) 2746–2756. [37] G.V. Plano, S.C. Straley, Journal of Bacteriology 177 (1995) 3843–3854. [38] C.J. Hueck, Microbiology and Molecular Biology Reviews 62 (1998) 379–433. [39] V. Molle, L. Kremer, C. Girard-Blanc, G.S. Besra, A.J. Cozzone, J.F. Prost, Biochemistry 42 (2003) 15300–15309. [40] K. Sharma, M. Gupta, A. Krupa, N. Srinivasan, Y. Singh, FEBS Journal 273 (2006) 2711–2721.
665
[41] A.E. Belanger, G.S. Besra, M.E. Ford, K. Mikusova, J.T. Belisle, P.J. Brennan, J.M. Inamine, Proceedings of the National Academy of Sciences of the United States of America 93 (1996) 11919–11924. [42] L.J. Alderwick, V. Molle, L. Kremer, A.J. Cozzone, T.R. Dafforn, G.S. Besra, K. Futterer, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 2558–2563. [43] V. Molle, R.C. Reynolds, L.J. Alderwick, G.S. Besra, A.J. Cozzone, K. Futterer, L. Kremer, The Biochemical Journal 410 (2008) 309–317. [44] S.V. Ramaswamy, A.G. Amin, S. Goksel, C.E. Stager, S.J. Dou, H. El Sahly, S.L. Moghazeh, B.N. Kreiswirth, J.M. Musser, Antimicrobial Agents and Chemotherapy 44 (2000) 326–336. [45] B.S. Goldman, W.C. Nierman, D. Kaiser, S.C. Slater, A.S. Durkin, J.A. Eisen, C.M. Ronning, W.B. Barbazuk, M. Blanchard, C. Field, C. Halling, G. Hinkle, O. Iartchuk, H.S. Kim, C. Mackenzie, R. Madupu, N. Miller, A. Shvartsbeyn, S.A. Sullivan, M. Vaudin, R. Wiegand, H.B. Kaplan, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 15200–15205. [46] K. Cho, D.R. Zusman, Molecular Microbiology 34 (1999) 714–725. [47] P.I. Higgs, S. Jagadeesan, P. Mann, D.R. Zusman, Journal of Bacteriology 190 (2008) 4416–4426. [48] E.H. Fischer, E.G. Krebs, Biochimica et Biophysica Acta 1000 (1989) 297–301. [49] Y. Av-Gay, M. Everett, Trends in Microbiology 8 (2000) 238–244. [50] S. Inouye, R. Jain, T. Ueki, H. Nariya, C.Y. Xu, M.Y. Hsu, B.A. Fernandez-Luque, J. Munoz-Dorado, E. Farez-Vidal, M. Inouye, Microbial & Comparative Genomics 5 (2000) 103–120. [51] M.A. Kotarski, D.A. Leonard, S.A. Bennett, C.P. Bishop, S.D. Wahn, S.A. Sedore, M. Shrader, Genome 41 (1998) 295–302. [52] E. Madec, A. Laszkiewicz, A. Iwanicki, M. Obuchowski, S. Seror, Molecular Microbiology 46 (2002) 571–586. [53] C.J. Bakal, J.E. Davies, Trends in Cell Biology 10 (2000) 32–38. [54] T. Umeyama, P.C. Lee, S. Horinouchi, Applied Microbiology and Biotechnology 59 (2002) 419–425. [55] R. Gross, B. Arico, R. Rappuoli, Molecular Microbiology 3 (1989) 1661–1667. [56] J.S. Parkinson, Cell 73 (1993) 857–871. [57] M. Braibant, P. Gilot, J. Content, FEMS Microbiology Reviews 24 (2000) 449–467. [58] J.M. Curry, R. Whalan, D.M. Hunt, K. Gohil, M. Strom, L. Rickman, M.J. Colston, S.J. Smerdon, R.S. Buxton, Infection and Immunity 73 (2005) 4471–4477. [59] C. Grundner, L.M. Gay, T. Alber, Protein Science 14 (2005) 1918–1921. [60] M.J. Canova, L. Kremer, V. Molle, Journal of Bacteriology 191 (2009) 2876–2883. [61] T. Alber, Current Opinion in Structural Biology 19 (2009) 650–657. [62] P. Barthe, C. Roumestand, M.J. Canova, L. Kremer, C. Hurard, V. Molle, M. Cohen-Gonsaud, Structure 17 (2009) 568–578. [63] B.Y. Qin, C. Liu, S.S. Lam, H. Srinath, R. Delston, J.J. Correia, R. Derynck, K. Lin, Natural Structural Biology 10 (2003) 913–921. [64] G.I. Lee, Z. Ding, J.C. Walker, S.R. Van Doren, Proceedings of the National Academy of Sciences of the United States of America 100 (2003) 11261–11266. [65] B.A. Joughin, B. Tidor, M.B. Yaffe, Protein Science 14 (2005) 131–139. [66] Y.S. Lee, J.H. Kim, S.T. Kim, J.Y. Kwon, S. Hong, S.J. Kim, S.H. Park, Biochemical and Biophysical Research Communications 393 (2010) 836–843. [67] W.C. Shakespeare, Current Opinion in Chemical Biology 5 (2001) 409–415. [68] C. Wang, L. Chen, L. Wang, J. Wu, Science in China. Series C, Life Sciences 52 (2009) 539–544. [69] R. Hao, L. Chen, J.W. Wu, Z.X. Wang, Acta Crystallographica. Section F, Structural Biology and Crystallization Communications 64 (2008) 986–990. [70] H.G. Xu, R. Jin, W. Ren, L. Zou, Y. Wang, G.P. Zhou, Biochimie 94 (2012) 1390–1397. [71] M. Sato, H. Suemori, N. Hata, M. Asagiri, K. Ogasawara, K. Nakao, T. Nakaya, M. Katsuki, S. Noguchi, N. Tanaka, T. Taniguchi, Immunity 13 (2000) 539–548. [72] C. Marian, R. Huang, R.F. Borch, Tetrahedron 67 (2011) 10216–10221. [73] W. Hao, Y. Hu, C. Niu, X. Huang, C.P. Chang, J. Gibbons, J. Xu, Bioorganic & Medicinal Chemistry Letters 18 (2008) 4988–4992. [74] M.Y. Yap, M.C. Wilce, D.J. Clayton, P. Perlmutter, M.I. Aguilar, J.A. Wilce, Acta Crystallographica. Section F, Structural Biology and Crystallization Communications 66 (2010) 1640–1643. [75] J. Wojcik, O. Hantschel, F. Grebien, I. Kaupe, K.L. Bennett, J. Barkinge, R.B. Jones, A. Koide, G. Superti-Furga, S. Koide, Nature Structural & Molecular Biology 17 (2010) 519–527. [76] G.M. Fuhler, R. Brooks, B. Toms, S. Iyer, E.A. Gengo, M.Y. Park, M. Gumbleton, D.R. Viernes, J.D. Chisholm, W.G. Kerr, Molecular Medicine 18 (2012) 65–75. [77] J.S. McMurray, P.K. Mandal, W.S. Liao, Z. Ren, X. Chen, Advances in Experimental Medicine and Biology 611 (2009) 545–546. [78] Y.M. Huang, M. Kang, C.E. Chang, The Journal of Physical Chemistry. B (2012). [79] N. Coquelle, R. Green, J.N. Glover, Biochemistry 50 (2011) 4579–4589. [80] W.D. Lehmann, R. Kruger, M. Salek, C.W. Hung, F. Wolschin, W. Weckwerth, Journal of Proteome Research 6 (2007) 2866–2873.
Contents lists available at SciVerse ScienceDirect
Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig
Review
Function and evolution of ubiquitous bacterial signaling adapter phosphopeptide recognition domain FHA Hong Weiling, Yu Xiaowen, Li Chunmei, Xie Jianping ⁎ Institute of Modern Biopharmaceuticals, State Key Laboratory breeding base of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Chongqing 400715, China
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Article history: Received 19 November 2012 Accepted 23 November 2012 Available online 29 November 2012 Keywords: FHA domain Phosphopeptide recognition Function Structure Evolution Distribution
a b s t r a c t Forkhead-associated domain (FHA) is a phosphopeptide recognition domain embedded in some regulatory proteins. With similar fold type to important eukaryotic signaling molecules such as Smad2 and IRF3, the role of bacterial FHA domain is intensively pursued. Reported bacterial FHA domain roles include: regulation of glutamate and lipids production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbohydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions. To provide basis for the studies of other bacterial FHA domain containing proteins, the status of bacterial FHA functionality and evolution were summarized. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction of FHA domain . . . . . . . . . . . . . . . . Evolution of FHA domain . . . . . . . . . . . . . . . . . . Structure of FHA domain . . . . . . . . . . . . . . . . . . Distribution of bacterial FHA domain . . . . . . . . . . . . Functionalities of FHA domain . . . . . . . . . . . . . . . 5.1. Regulation of glutamate production . . . . . . . . . 5.2. Increase of lipid level . . . . . . . . . . . . . . . . 5.3. Regulation of cell shape . . . . . . . . . . . . . . . 5.4. Type III secretion . . . . . . . . . . . . . . . . . . 5.5. Ethambutol resistance . . . . . . . . . . . . . . . . 5.6. Sporulation . . . . . . . . . . . . . . . . . . . . . 6. Regulation of FHA domain activity . . . . . . . . . . . . . 6.1. Phosphorylation activity of the FHA-containing protein 6.2. Phosphorylation inhibits the FHA-containing protein . 7. Analogs of FHA domain—MH2 . . . . . . . . . . . . . . . 8. Significance of FHA domain . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction of FHA domain FHA is phosphopeptide recognition domain present in some regulatory proteins, bearing ubiquitous phosphothreonine-dependent binding ⁎ Corresponding author. Tel./fax: +86 23 68367108. E-mail address: [email protected] (X. Jianping).
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module or phosphotyrosine-dependent binding module. The affinity of the former is higher than the latter [1]. Phosphopeptide recognition protein is a major player in signaling [2]. In eukaryotes, many FHA domain-containing proteins localize at the nucleus and function in the establishment of maintenance of cell cycle checkpoints, DNA repair, or transcriptional regulation [3]. FHA is a well known ubiquitous phosphothreonine-dependent binding module. However, their function
0898-6568/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cellsig.2012.11.019
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in bacterial physiology and signaling remained largely obscure until 2002[4]. FHA-containing proteins are found widespread among bacteria, such as Myxococcus xanthus, Deinococcus radiodurans, Anabaena, Bacillus halodurans, Synechocystis, Streptomyces coelicolor, Pseudomonas aeruginosa, Agrobacterium tumefaciens, Sulfolobus acidocaldarius, and Sulfolobus tokodaii [5–10]. FHA domain roles in bacteria have been characterized: glutamate and lipid production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbohydrate storage and transport, pathogenic and symbiotic host–bacterium interactions [11–14]. This study aims to summarize FHA functionality and evolution. 2. Evolution of FHA domain The origin of FHA domain is intriguing. For intracellular parasites, the putative FHA-containing proteins might obtain genes encoding FHA-containing proteins from their eukaryotic hosts. However, FHA-containing proteins are also found in a other free-living bacteria, such as D. radiodurans, M. xanthus, Anabaena, Synechocystis, P. aeruginosa, B. halodurans, S. coelicolor and A. tumefaciens (http://pfam.sanger.ac.uk/ family/FHA). The presence of FHA domains in proteobacteria and cyanobacteria implicates that eukaryotic FHA domains might have evolved from nuclear-transferred genes of endosymbionts [15,16]. Whatever the origin of bacterial FHA domains is, the modular phosphopeptide recognition might undergo several times during evolution to meet its biological roles [17]. The ancient FHA domain module [18] might have been replaced by other phosphopeptide-binding module during evolution [19], as evidenced by the PinA protein of Dictyostelium discoideum, a peptidyl-prolyl isomerase of the Pin1 family [17]. Unlike its cognate eukaryotic phosphopeptide-binding domain, DdPinA lacks the phosphopeptide-binding WW domain in its N-terminus [17]. Fig. 1 is the phylogeny of FHA-containing bacteria.
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divergent spacer regions: GR, SXXH, and NG[1]. FHA domain contains 11-stranded beta sandwich, with small helical insertions at the loops connecting the strands [20]. The conserved blocks usually distributed as following: GR at the end of strand three, SXXH before strand five and NG before strand seven [17]. Fig. 2 is the characteristic structure of FHA domain. 4. Distribution of bacterial FHA domain The ubiquitous of FHA domains among bacteria does not necessarily mean there existence in all bacteria. However, three categories do have FHA domains, namely the mycobacteria, the cyanobacteria, some Gram-negative proteobacteria and the chlamydias [4]. Table 1 is the distribution of the bacterial FHA domain. 5. Functionalities of FHA domain FHA domain has been implicated in the glutamate and lipid production, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbonhydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions. Fig. 3 is the schematic representation of the roles of bacterial FHA domains. 5.1. Regulation of glutamate production Corynebacterium glutamicum, a Gram-positive soil bacterium, is an industrial producer of multiple products [22]. Arabinose-inducible expression system regulated expression of C. glutamicum OdhI gene can change the yields of glutamate under biotin non-limiting conditions [23]. OdhI gene product contains FHA domain and is an inhibitor of alpha-oxoglutarate dehydrogenase [24]. 5.2. Increase of lipid level
3. Structure of FHA domain The representative FHA domain contains approximately 55–75 amino acids with three highly conserved blocks separated by some
Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis [25]. Rv0019c (fhaB, Forkhead-associated domain-containing protein), a putative virulence factor, is involved in regulating cell shape
Fig. 1. Phylogeny of FHA-containing bacteria. Phylogeny reveals the diversity of FHA-containing bacteria. FHA domains are found in a wide range of bacteria including bacillus, coccus and vibrio. Two FHA-containing proteins are similar in P. aeruginosa. The FHA-containing protein in A. tumefaciens and R. leguminosarum resembles each other. The lower similarity of FHA-containing protein in the same bacterium than those from two bacteria indicates that FHA domain is not a good taxonomy marker for bacteria.
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Fig. 2. Characteristic structure of FHA domain. Yellow indicates the identical sequences. Mtb is the abbreviation of Mycobacterium tuberculosis. EmbR, fhaB and GarA are the FHA containing protein in M. tuberculosis. Three highly conserved blocks: GR, SXXH, and NG. Blue arrow represents 11-stranded beta sandwich.
[26]. Rv0019c can interact with polyketide-associated protein PapA5, a putative membrane protein involved in the biosynthesis of virulence enhancing lipids [27,28]. Rv0019c FHA domain was reported to mediate the interaction with PapA5. This FHA domain was identified as novel phophoindependent binding surface [26].
interaction between the protein–phosphoprotein regulating the arabinan synthesis [42]. One possible scenario is that pknH phosphorylates embR, which is then activated through an FHA-mediated interaction [43]. Intriguingly, an ethambutol resistance mutation occurred at a residue within the EmbR FHA domain, indicating that modification of FHA-mediated interactions can cause an ethambutol-resistance [44].
5.3. Regulation of cell shape 5.6. Sporulation Clostridium acetobutylicum was tagged as the “Weizmann Organism”, and can produce acetone, ethanol, and butanol from starch simultaneously [29]. CAC0504 in rodA/pbp gene cluster is involved in the regulation of cell shape [30]. OdhI gene encodes an inhibitor of alphaoxoglutarate dehydrogenase. FtsZ is a wide distributed cytoskeletal protein involved in the archaeal and bacterial cell division. OdhI and FtsZ are substrates of PknA, PknB and PknL. This suggested that the OdhI might engage in the cell division [31].
M. xanthus, with a complex starvation-induced developmental program that cause starving bacteria self-organize to form fruiting bodies, is a model organism for development [45]. EspA is a histidine protein kinase with a FHA domain at the N-terminus [46]. EspA is part of a two-component signal transduction system that regulates the timing of sporulation. EspA mutants, encoding a deformed hybrid histidine kinase, change the timing of developmental program [46]. This shows that EspA plays a significant role in the sporulation [47].
5.4. Type III secretion 6. Regulation of FHA domain activity Chlamydia trachomatis is a Gram-negative bacteria [32], an obligate intracellular human pathogen leading to urethritis, proctitis, trachoma and infertility [33–35]. CT664 encodes a single FHA-domain-containing protein found in three chlamydial species. The gene encoding this protein situates within the type III secretion system cluster that also encodes an STPK (CT673 in C. trachomatis) [36], suggesting a role of CT664 in the chlamydial type III secretion system by mediating phosphorylationdependent protein–protein interactions [37,38]. 5.5. Ethambutol resistance EmbR (encoded by Rv1267) is adjacent to a cluster of ATP-binding cassette transporter genes and pknH [39,40]. Rv1267 contains carboxy-terminal FHA domain and is a transcriptional regulator of the embA and embB genes, which encode cell wall arabinosyl transferases related to ethambutol resistance [41]. This FHA domain mediates the
The serine/threonine protein kinases were widely recognized as eukaryote unique proteins [48] until the discovery of their occurrence in prokaryotes [49–52]. These protein kinases were assigned similar roles in signal transduction [53,54] as those “two-component systems” sensor histidine kinases [55,56]. 6.1. Phosphorylation activity of the FHA-containing protein M. tuberculosis Rv1747, a predicted ATP-binding cassette transporter essential for its in vivo growth, contains two FHA domains [57,58]. PknF can also phosphorylate Rv1747 on two specific threonine residues, namely Thr-150 and Thr-208 [21]. Other FHA-containing proteins are Rv0020c and the heat-shock protein GroEL1 [59,60]. Rv1747 mutation of threonine-to-alanine can alter infection outcome. This implicates that phosphorylation can alter
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Table 1 Distribution of the bacterial FHA domain. Protein (length)
Organism
FHA domain
Associated STPK/STPPs
Comments
fhaB (155)
Mycobacterium tuberculosis
57–149
STPK: pknA/pknB STPP: ppp STPK: pknA/pknB, STPP: ppp STPK: pknH
In rodA/pbp gene cluster; involved in regulating cell shape
fhaA (527)
389–525
Rv1267c (388)
257–380
Rv1747 (865)
177–299
STPK: pknE/pknF Thr-150 and Thr-208
Rv1827 (162) Rv3360 (122) OdhI (143) BH1777 (230) DRA0333 (314) CAC0036 (468)
35–156 4–92 49–138 18–102 167–311 379–468
STPK: pknG/pknB
CAC0039 (1544)
111–201
STPP: CAC0035
CAC0406 (516)
420–516
CAC0408 (1524)
82–190
STPP: CAC0407 STPK: CAC0404 STPP: CAC0407 STPK: CAC0404
CAC0504 (159) SCH69.13 (290)
Corynebacterium glutamicum Bacillus halodurans Deinococcus radiodurans Clostridium acetobutylicum
Streptomyces coelicolor
84–158 159–286
BH2504 STPK: DRA0332 STPP: CAC0035
STPK: SCH69.18 STPP: SCH69.15 STPK: SCH69.18 STPP: SCH69.15
SCH69.14 (172)
46–168
SC1A8A.04c (267) SCE50.03 (1345)
141–260 94–201
SCBAC1A6.03 (183) SC6D10.12 (604)
102–179 452–594
Two STPKs
SCI33.05c (876)
1–89, 201–307
STPP
25–107
STPP: stp1 STPK: stk1 STPP: PA0075, STPK: ppkA STPP: impM STPK: impN STPP: AGR_L_1064, TPK: AGR_L_1065 STPP: mlr2361, STPK: mlr2363 No STPK in genome No STPK in genome STPK: pkn3
PA1665 (397)
Pseudomonas aeruginosa PAO1
PA0081 (497)
23–121 15–113
AGR_L_1057 (399)
Rhizobium leguminosarum bv. trifolii Agrobacterium tumefaciens
mlr2345 (486) Ecs0229 (616) vca0112 (495) orf1 (833)
Mesorhizobium loti Escherichia coli O157 Vibrio cholerae Myxococcus xanthus
13–106
ImpI (399)
EspA (388) CT664 (768) YscD (829)
Chlamydia trachomatis Yersinia enterocolitica
28–113
18–120 8–108 136–279, 271–385 32–148 355–476
STPK: pkaA/pkaB
STPK: CT673
the activity of Rv1747, thereby effecting the growth of M. tuberculosis [21].
6.2. Phosphorylation inhibits the FHA-containing protein Unphosphorylated FHA-domain protein GarA regulates primary metabolism, while phosphorylated one can mediate the GarA autoinhibition [61]. Solution structures of the unphosphorylated and phosphorylated demonstrated major conformational difference between the two forms [10]. GarA can bind its own phosphorylated N-terminal of the FHA domain to self-inhibit [61]. This represents a new autoinhibition mechanism in FHA domain protein [62].
In rodA/pbp gene cluster; involved in regulating cell shape EmbR; contains an amino-terminal BAD domain; regulates cell wall arabinosyltransferases; involved in ethambutol resistance; adjacent cluster of ABC transporter genes ABC transporter that is necessary for growth of M. tuberculosis in vivo and contains two Forkhead-associated (FHA) domains[21]. GarA; implicated in regulation of glycogen storage No functional assignment Contains carboxy-terminal DNA-binding domain Contains Ala/Pro-rich low-complexity sequence Contains TM domain; clusters with WXG100 and acetobutylicum tetratricopeptide repeat genes Contains TM domain and three SpoIIIE/FtsK domains; clusters with WXG100 and tetratricopeptide repeat genes Contains TM domain; clusters with WXG100 and etratricopeptide repeat genes Contains TM domain and three SpoIIIE/FtsK domains; clusters with WXG100 and tetratricopeptide repeat genes In rodA/pbp gene cluster; involved in regulating cell shape? Orthologue of Rv0020c Orthologue of Rv0019c Orthologue of GarA Contains proline-rich low-complexity sequence; contains FtsK/SpoIIIE domain; adjacent cluster of ABC transporter genes Clusters with amylase genes; involved in glycogen metabolism? Contains low-complexity proline-rich sequence; in sugar transport system operon; regulates uptake of unidentified carbohydrate? Contains two amino-terminal FHA domains flanking proline-rich low-complexity sequence, followed by an ABC-transporter domain and TM domains In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster In impA-N-like gene cluster; in O-island In impA-N-like gene cluster Contains a proline-rich amino-terminal domain followed by two FHA domains Histidine-kinase; a complex domain architecture; regulates the timing of sporulation In type III secretion gene cluster, see below Amino-terminal putative FHA domain also evident in some other SctD proteins, e.g. PscD from Pseudomonas aeruginosa, HrpQ from Erwinia amylovora
7. Analogs of FHA domain—MH2 Intriguingly, the fold of the FHA domain is extremely similar to the bend of the Smad MH2 domain [63–65]. The MH2 domain of Smad transcriptional regulators plays a crucial role in Smad-dependent TGFL signaling and serves as a binding interface for the tetra-phosphorylated type I TGFL receptor (TLR-I) [66]. The conserved fold might demonstrate functional conservation [67]. Mapping of the interaction determinants on the MH2 domain suggested that the region required for the interaction of MH2 is similar to the phosphopeptide interaction region of FHA domains [67–69]. This striking similarity leads to the possibility that the FHA and MH2 domains might share a common ancestor which has a phosphopeptide-binding activity [67].
664
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Fig. 3. Schematic representation of the roles of bacterial FHA domains. (A) Schematic representation of bacterial FHA domain roles: Glutamate production, lipids increased, regulation of cell shape, type III secretion, ethambutol resistance, and sporulation are well documented roles of FHA domain. EspA: putative histidine protein kinase; FruA: putative response regulator that governs a branched signaling pathway inside cells; OdhA: alpha-oxoglutarate dehydrogenase A; OdhI: alpha-oxoglutarate dehydrogenase I; PknG: Serine/threonine-protein kinase G; PknB: Serine/threonine-protein kinase B; Pap5: polyketide-associated Protein 5; fhaB: Forkhead-associated domain B; PDIM: phthiodiolone dimycocerosate esters; YscD: Yop secretion D; syc: cytoplasmic chaperones; (B) and (C):locations of FHA domains in FHA-containing protein. Trans-reg-C: Transcriptional regulatory protein, C terminal; DUF1706: Protein of unknown function. This family contains many hypothetical proteins from bacteria and yeast; PAS: putative active site domain; Response-reg: Response regulator receiver domain; MARCKS: MARCKS family; Type-III-yscD: type III secretion apparatus protein, YscD/HrpQ family; ABCG-EPDR: Eye pigment and drug resistance transporter subfamily G of the ATP-binding cassette superfamily; ABC2-membrane: ABC-2 type transporter; SalX: ABC-type antimicrobial peptide transport system, ATPase component.
IRF-3, a member of the interferon regulatory factor (IRF) family, plays an important role in the development of the IFN antiviral response [70,71]. IRF-3 shares a marked structural similarity to the MH2 domain and the FHA domain, indicating a common molecular mechanism of action among these domains of signaling mediators [63].
[11–14]. The structural continuum of phosphopeptide recognition modules provides a basis for incremental phosphopeptide activity inhibition [78–80]. Therapeutic inhibitors of FHA domains active in bacteria might be promising novel antibiotics and tool compounds to dissect FHA-dependent processes in vivo.
8. Significance of FHA domain Acknowledgments SH2 domain inhibitors such as 1,4-cis-enediol scaffold, 1,2dihydroxybenzene, G7-18NATE cyclic peptide, and specific FN3 monobody might be good medications against various pathogens [72–77]. With the recent progress in effective anti-SH2 compounds [47,48], intensive studies are directed to identify similar anti-FHA molecules capable of blocking signal-dependent protein–protein interactions. Bacterial FHA domain are involved in glutamate production, lipid accumulation, regulation of cell shape, type III secretion, ethambutol resistance, sporulation, signal transduction, carbonhydrate storage and transport, and pathogenic and symbiotic host–bacterium interactions
This work was funded by the National Natural Science Foundation (Grant No. 81071316 and No.81271882), National Megaprojects for Key Infectious Diseases (No.2008ZX10003-006), New Century Excellent Talents in Universities (NCET-11-0703), Excellent PhD Thesis Fellowship of Southwest University (Grant Nos. kb2009010 and ky2011003), the Fundamental Research Funds for the Central Universities) Grant No. XDJK2012D011, XDJK2011C020, XDJK2013D003 and XDJK2012D007), and Natural Science Foundation Project of CQ CSTC (Grant No. CSTC, 2010BB5002).
H. Weiling et al. / Cellular Signalling 25 (2013) 660–665
References [1] K. Hofmann, P. Bucher, Trends in Biochemical Sciences 20 (1995) 347–349. [2] S. Richter, V. Bouvet, M. Wuest, R. Bergmann, J. Steinbach, J. Pietzsch, I. Neundorf, F. Wuest, Nuclear Medicine and Biology 39 (2012) 1202–1212. [3] D. Durocher, I.A. Taylor, D. Sarbassova, L.F. Haire, S.L. Westcott, S.P. Jackson, S.J. Smerdon, M.B. Yaffe, Molecular Cell 6 (2000) 1169–1182. [4] M. Pallen, R. Chaudhuri, A. Khan, Trends in Microbiology 10 (2002) 556–563. [5] L. Jelsbak, M. Givskov, D. Kaiser, Proceedings of the National Academy of Sciences of the United States of America 102 (2005) 3010–3015. [6] G. Jones, R. Del Sol, E. Dudley, P. Dyson, Microbial Biotechnology 4 (2011) 263–274. [7] F. Hsu, S. Schwarz, J.D. Mougous, Molecular Microbiology 72 (2009) 1111–1125. [8] J.D. Mougous, C.A. Gifford, T.L. Ramsdell, J.J. Mekalanos, Nature Cell Biology 9 (2007) 797–803. [9] J. Reimann, K. Lassak, S. Khadouma, T.J. Ettema, N. Yang, A.J. Driessen, A. Klingl, S.V. Albers, Molecular Microbiology 86 (2012) 24–36. [10] X. Duan, Z.G. He, Biochemical and Biophysical Research Communications 407 (2011) 242–247. [11] D.L. Johnson, J.B. Mahony, Journal of Bacteriology 189 (2007) 7549–7555. [12] M.D. Tsai, Structure 10 (2002) 887–888. [13] M.A. McDowell, S. Johnson, J.E. Deane, M. Cheung, A.D. Roehrich, A.J. Blocker, J.M. McDonnell, S.M. Lea, The Journal of Biological Chemistry 286 (2011) 30606–30614. [14] J.A. Ross, G.V. Plano, Journal of Bacteriology 193 (2011) 2276–2289. [15] V.V. Emelyanov, FEBS Letters 501 (2001) 11–18. [16] J. Falck, C. Lukas, M. Protopopova, J. Lukas, G. Selivanova, J. Bartek, Oncogene 20 (2001) 5503–5510. [17] D. Durocher, S.P. Jackson, FEBS Letters 513 (2002) 58–66. [18] B. Wang, S. Yang, L. Zhang, Z.G. He, Journal of Bacteriology 192 (2010) 1956–1964. [19] R.A. Cigliano, W. Sanseverino, G. Cremona, F.M. Consiglio, C. Conicella, BMC Evolutionary Biology 11 (2011) 78. [20] H. Liao, I.J. Byeon, M.D. Tsai, Journal of Molecular Biology 294 (1999) 1041–1049. [21] V.L. Spivey, V. Molle, R.H. Whalan, A. Rodgers, J. Leiba, L. Stach, K.B. Walker, S.J. Smerdon, R.S. Buxton, The Journal of Biological Chemistry 286 (2011) 26198–26209. [22] M.D. Collins, L. Hoyles, G. Foster, E. Falsen, International Journal of Systematic and Evolutionary Microbiology 54 (2004) 925–928. [23] Y. Zhang, X. Shang, S. Lai, G. Zhang, Y. Liang, T. Wen, Applied and Environmental Microbiology (2012). [24] A. Niebisch, A. Kabus, C. Schultz, B. Weil, M. Bott, The Journal of Biological Chemistry 281 (2006) 12300–12307. [25] P. Sudre, G. ten Dam, A. Kochi, Bulletin of the World Health Organization 70 (1992) 149–159. [26] M. Gupta, A. Sajid, G. Arora, V. Tandon, Y. Singh, The Journal of Biological Chemistry 284 (2009) 34723–34734. [27] O.A. Trivedi, P. Arora, A. Vats, M.Z. Ansari, R. Tickoo, V. Sridharan, D. Mohanty, R.S. Gokhale, Molecular Cell 17 (2005) 631–643. [28] K.C. Onwueme, J.A. Ferreras, J. Buglino, C.D. Lima, L.E. Quadri, Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 4608–4613. [29] L.K. Bowles, W.L. Ellefson, Applied and Environmental Microbiology 50 (1985) 1165–1170. [30] R. Chaba, M. Raje, P.K. Chakraborti, European journal of biochemistry/FEBS 269 (2002) 1078–1085. [31] C. Schultz, A. Niebisch, A. Schwaiger, U. Viets, S. Metzger, M. Bramkamp, M. Bott, Molecular Microbiology 74 (2009) 724–741. [32] C. Benson, J. Segreti, H. Kessler, D. Hines, L. Goodman, R. Kaplan, G. Trenholme, European Journal of Clinical Microbiology 6 (1987) 173–178. [33] A. Balakrishnan, B. Patel, S.A. Sieber, D. Chen, N. Pachikara, G. Zhong, B.F. Cravatt, H. Fan, The Journal of Biological Chemistry 281 (2006) 16691–16699. [34] T.C. Quinn, S.E. Goodell, E. Mkrtichian, M.D. Schuffler, S.P. Wang, W.E. Stamm, K.K. Holmes, The New England Journal of Medicine 305 (1981) 195–200. [35] J. Henry-Suchet, F. Catalan, V. Loffredo, D. Serfaty, A. Siboulet, Y. Perol, M.J. Sanson, C. Debache, F. Pigeau, R. Coppin, J. de Brux, T. Poynard, American Journal of Obstetrics and Gynecology 138 (1980) 1022–1025. [36] E. Lorenzini, A. Singer, B. Singh, R. Lam, T. Skarina, N.Y. Chirgadze, A. Savchenko, R.S. Gupta, Journal of Bacteriology 192 (2010) 2746–2756. [37] G.V. Plano, S.C. Straley, Journal of Bacteriology 177 (1995) 3843–3854. [38] C.J. Hueck, Microbiology and Molecular Biology Reviews 62 (1998) 379–433. [39] V. Molle, L. Kremer, C. Girard-Blanc, G.S. Besra, A.J. Cozzone, J.F. Prost, Biochemistry 42 (2003) 15300–15309. [40] K. Sharma, M. Gupta, A. Krupa, N. Srinivasan, Y. Singh, FEBS Journal 273 (2006) 2711–2721.
665
[41] A.E. Belanger, G.S. Besra, M.E. Ford, K. Mikusova, J.T. Belisle, P.J. Brennan, J.M. Inamine, Proceedings of the National Academy of Sciences of the United States of America 93 (1996) 11919–11924. [42] L.J. Alderwick, V. Molle, L. Kremer, A.J. Cozzone, T.R. Dafforn, G.S. Besra, K. Futterer, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 2558–2563. [43] V. Molle, R.C. Reynolds, L.J. Alderwick, G.S. Besra, A.J. Cozzone, K. Futterer, L. Kremer, The Biochemical Journal 410 (2008) 309–317. [44] S.V. Ramaswamy, A.G. Amin, S. Goksel, C.E. Stager, S.J. Dou, H. El Sahly, S.L. Moghazeh, B.N. Kreiswirth, J.M. Musser, Antimicrobial Agents and Chemotherapy 44 (2000) 326–336. [45] B.S. Goldman, W.C. Nierman, D. Kaiser, S.C. Slater, A.S. Durkin, J.A. Eisen, C.M. Ronning, W.B. Barbazuk, M. Blanchard, C. Field, C. Halling, G. Hinkle, O. Iartchuk, H.S. Kim, C. Mackenzie, R. Madupu, N. Miller, A. Shvartsbeyn, S.A. Sullivan, M. Vaudin, R. Wiegand, H.B. Kaplan, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 15200–15205. [46] K. Cho, D.R. Zusman, Molecular Microbiology 34 (1999) 714–725. [47] P.I. Higgs, S. Jagadeesan, P. Mann, D.R. Zusman, Journal of Bacteriology 190 (2008) 4416–4426. [48] E.H. Fischer, E.G. Krebs, Biochimica et Biophysica Acta 1000 (1989) 297–301. [49] Y. Av-Gay, M. Everett, Trends in Microbiology 8 (2000) 238–244. [50] S. Inouye, R. Jain, T. Ueki, H. Nariya, C.Y. Xu, M.Y. Hsu, B.A. Fernandez-Luque, J. Munoz-Dorado, E. Farez-Vidal, M. Inouye, Microbial & Comparative Genomics 5 (2000) 103–120. [51] M.A. Kotarski, D.A. Leonard, S.A. Bennett, C.P. Bishop, S.D. Wahn, S.A. Sedore, M. Shrader, Genome 41 (1998) 295–302. [52] E. Madec, A. Laszkiewicz, A. Iwanicki, M. Obuchowski, S. Seror, Molecular Microbiology 46 (2002) 571–586. [53] C.J. Bakal, J.E. Davies, Trends in Cell Biology 10 (2000) 32–38. [54] T. Umeyama, P.C. Lee, S. Horinouchi, Applied Microbiology and Biotechnology 59 (2002) 419–425. [55] R. Gross, B. Arico, R. Rappuoli, Molecular Microbiology 3 (1989) 1661–1667. [56] J.S. Parkinson, Cell 73 (1993) 857–871. [57] M. Braibant, P. Gilot, J. Content, FEMS Microbiology Reviews 24 (2000) 449–467. [58] J.M. Curry, R. Whalan, D.M. Hunt, K. Gohil, M. Strom, L. Rickman, M.J. Colston, S.J. Smerdon, R.S. Buxton, Infection and Immunity 73 (2005) 4471–4477. [59] C. Grundner, L.M. Gay, T. Alber, Protein Science 14 (2005) 1918–1921. [60] M.J. Canova, L. Kremer, V. Molle, Journal of Bacteriology 191 (2009) 2876–2883. [61] T. Alber, Current Opinion in Structural Biology 19 (2009) 650–657. [62] P. Barthe, C. Roumestand, M.J. Canova, L. Kremer, C. Hurard, V. Molle, M. Cohen-Gonsaud, Structure 17 (2009) 568–578. [63] B.Y. Qin, C. Liu, S.S. Lam, H. Srinath, R. Delston, J.J. Correia, R. Derynck, K. Lin, Natural Structural Biology 10 (2003) 913–921. [64] G.I. Lee, Z. Ding, J.C. Walker, S.R. Van Doren, Proceedings of the National Academy of Sciences of the United States of America 100 (2003) 11261–11266. [65] B.A. Joughin, B. Tidor, M.B. Yaffe, Protein Science 14 (2005) 131–139. [66] Y.S. Lee, J.H. Kim, S.T. Kim, J.Y. Kwon, S. Hong, S.J. Kim, S.H. Park, Biochemical and Biophysical Research Communications 393 (2010) 836–843. [67] W.C. Shakespeare, Current Opinion in Chemical Biology 5 (2001) 409–415. [68] C. Wang, L. Chen, L. Wang, J. Wu, Science in China. Series C, Life Sciences 52 (2009) 539–544. [69] R. Hao, L. Chen, J.W. Wu, Z.X. Wang, Acta Crystallographica. Section F, Structural Biology and Crystallization Communications 64 (2008) 986–990. [70] H.G. Xu, R. Jin, W. Ren, L. Zou, Y. Wang, G.P. Zhou, Biochimie 94 (2012) 1390–1397. [71] M. Sato, H. Suemori, N. Hata, M. Asagiri, K. Ogasawara, K. Nakao, T. Nakaya, M. Katsuki, S. Noguchi, N. Tanaka, T. Taniguchi, Immunity 13 (2000) 539–548. [72] C. Marian, R. Huang, R.F. Borch, Tetrahedron 67 (2011) 10216–10221. [73] W. Hao, Y. Hu, C. Niu, X. Huang, C.P. Chang, J. Gibbons, J. Xu, Bioorganic & Medicinal Chemistry Letters 18 (2008) 4988–4992. [74] M.Y. Yap, M.C. Wilce, D.J. Clayton, P. Perlmutter, M.I. Aguilar, J.A. Wilce, Acta Crystallographica. Section F, Structural Biology and Crystallization Communications 66 (2010) 1640–1643. [75] J. Wojcik, O. Hantschel, F. Grebien, I. Kaupe, K.L. Bennett, J. Barkinge, R.B. Jones, A. Koide, G. Superti-Furga, S. Koide, Nature Structural & Molecular Biology 17 (2010) 519–527. [76] G.M. Fuhler, R. Brooks, B. Toms, S. Iyer, E.A. Gengo, M.Y. Park, M. Gumbleton, D.R. Viernes, J.D. Chisholm, W.G. Kerr, Molecular Medicine 18 (2012) 65–75. [77] J.S. McMurray, P.K. Mandal, W.S. Liao, Z. Ren, X. Chen, Advances in Experimental Medicine and Biology 611 (2009) 545–546. [78] Y.M. Huang, M. Kang, C.E. Chang, The Journal of Physical Chemistry. B (2012). [79] N. Coquelle, R. Green, J.N. Glover, Biochemistry 50 (2011) 4579–4589. [80] W.D. Lehmann, R. Kruger, M. Salek, C.W. Hung, F. Wolschin, W. Weckwerth, Journal of Proteome Research 6 (2007) 2866–2873.