helix turn helix motifs


Summary: The first DNA-binding protein motif to be recognized. Helix-turn-helix motifs were originally identified in bacterial proteins but have since been found in hundreds of DNA-BINDING PROTEINS from both eukaryotes and prokaryotes. They are constructed from two alpha helices connected by a short extended chain of amino acids, which constitute the "turn." The two helices are held at a fixed angle, primarily through interactions between the two helices. (From Alberts et al., Molecular Biology of the Cell, 3d ed, p408-9)

Top Publications

  1. Littlefield O, Korkhin Y, Sigler P. The structural basis for the oriented assembly of a TBP/TFB/promoter complex. Proc Natl Acad Sci U S A. 1999;96:13668-73 pubmed
    ..This interaction is important in determining the level of basal transcription and explicitly defines the direction of transcription...
  2. Ferrer Costa C, Shanahan H, Jones S, Thornton J. HTHquery: a method for detecting DNA-binding proteins with a helix-turn-helix structural motif. Bioinformatics. 2005;21:3679-80 pubmed
    ..HTHquery is implemented using a set of Perl scripts and C program and can be accessed freely on the website http://www.ebi.ac.uk/thornton-srv/databases/HTHquery. ..
  3. Morant Lhomel A, René B, Zargarian L, Troalen F, Mauffret O, Fermandjian S. Self-association and DNA binding properties of the human topoisomerase IIA alpha2HTH module. Biochimie. 2006;88:253-63 pubmed
    ..The module may thus be used for the search of drugs efficient in hindering topoisomerase II dimerization or binding to DNA. ..
  4. McLaughlin W, Berman H. Statistical models for discerning protein structures containing the DNA-binding helix-turn-helix motif. J Mol Biol. 2003;330:43-55 pubmed
  5. Ravin N, Rech J, Lane D. Mapping of functional domains in F plasmid partition proteins reveals a bipartite SopB-recognition domain in SopA. J Mol Biol. 2003;329:875-89 pubmed
    ..Evidence for the involvement of the SopA N terminus in autoinhibition of SopA function was obtained, revealing a possible new aspect of the role of SopB in SopA activation. ..
  6. Jones S, Barker J, Nobeli I, Thornton J. Using structural motif templates to identify proteins with DNA binding function. Nucleic Acids Res. 2003;31:2811-23 pubmed
    ..5% by introducing an accessible surface area threshold value of 990 A2 per HTH motif. The template library and the validated thresholds were used to make predictions for target proteins from a structural genomics project. ..
  7. Figge R, Easter J, Gober J. Productive interaction between the chromosome partitioning proteins, ParA and ParB, is required for the progression of the cell cycle in Caulobacter crescentus. Mol Microbiol. 2003;47:1225-37 pubmed
    ..We hypothesize that the amino-terminus of ParB is required to regulate the nucleotide exchange of ParA which, in turn, regulates the initiation of cell division. ..
  8. Roy S, Sahu A, Adhya S. Evolution of DNA binding motifs and operators. Gene. 2002;285:169-73 pubmed
    ..We have discussed current evidence for monophyletic or polyphyletic origin of such sequences. ..
  9. Iwahara J, Iwahara M, Daughdrill G, Ford J, Clubb R. The structure of the Dead ringer-DNA complex reveals how AT-rich interaction domains (ARIDs) recognize DNA. EMBO J. 2002;21:1197-209 pubmed
    ..The prevalence of serine amino acids at all specificity determining positions suggests that ARIDs within SWI/SNF-related complexes will interact with DNA non-sequence specifically. ..

More Information


  1. Pellegrini Calace M, Thornton J. Detecting DNA-binding helix-turn-helix structural motifs using sequence and structure information. Nucleic Acids Res. 2005;33:2129-40 pubmed
  2. Iwahara J, Clubb R. Solution structure of the DNA binding domain from Dead ringer, a sequence-specific AT-rich interaction domain (ARID). EMBO J. 1999;18:6084-94 pubmed
    ..Primary homology suggests that all ARID-containing proteins contact DNA through the HTH and hairpin structures, but only extended-ARID proteins supplement this binding surface with a terminal helix. ..
  3. Rosinski J, Atchley W. Molecular evolution of helix-turn-helix proteins. J Mol Evol. 1999;49:301-9 pubmed
    ..The consequences of such an origin for a diverse group of proteins, and guidelines for the identification of future members of the HTH family are discussed. ..
  4. Littlefield O, Nelson H. A new use for the 'wing' of the 'winged' helix-turn-helix motif in the HSF-DNA cocrystal. Nat Struct Biol. 1999;6:464-70 pubmed
    ..This dimer interface is likely important for increasing the DNA-binding specificity and affinity of the trimeric form of HSF, as well as for increasing cooperativity between adjacent trimers. ..
  5. White A, Ding X, vanderSpek J, Murphy J, Ringe D. Structure of the metal-ion-activated diphtheria toxin repressor/tox operator complex. Nature. 1998;394:502-6 pubmed
    ..We propose that a metal-ion-induced helix-to-coil structural transition in the amino-terminal region of the protein is partly responsible for the unique mode of repressor activation by transition metal ions. ..
  6. Shanahan H, Garcia M, Jones S, Thornton J. Identifying DNA-binding proteins using structural motifs and the electrostatic potential. Nucleic Acids Res. 2004;32:4732-41 pubmed
    ..Similar true positive fractions are achieved for the HhH and HLH motifs. We see evidence of wide evolutionary diversity for DNA-binding proteins with an HTH motif, and much smaller diversity for those with an HhH or HLH motif. ..
  7. Dueber E, Corn J, Bell S, Berger J. Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex. Science. 2007;317:1210-3 pubmed publisher
    ..Biochemical and comparative analyses indicate that AAA+/DNA contacts observed in the structure are dynamic and evolutionarily conserved, suggesting that the complex forms a core component of the basal initiation machinery...
  8. Aravind L, Anantharaman V, Balaji S, Babu M, Iyer L. The many faces of the helix-turn-helix domain: transcription regulation and beyond. FEMS Microbiol Rev. 2005;29:231-62 pubmed
    ..This differential relationship of their basal and specific transcriptional machinery poses an apparent conundrum regarding the origins of their transcription apparatus. ..
  9. Tubbs J, Pegg A, Tainer J. DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy. DNA Repair (Amst). 2007;6:1100-15 pubmed
  10. Onaka H, Ando N, Nihira T, Yamada Y, Beppu T, Horinouchi S. Cloning and characterization of the A-factor receptor gene from Streptomyces griseus. J Bacteriol. 1995;177:6083-92 pubmed
    ..The presence of ArpA-like proteins among Streptomyces spp., as revealed by PCR, together with the presence of A-factor-like compounds, suggests that a hormonal control similar to the A-factor system exists in many species of this genus...
  11. Werner M, Clore M, Fisher C, Fisher R, Trinh L, Shiloach J, et al. The solution structure of the human ETS1-DNA complex reveals a novel mode of binding and true side chain intercalation. Cell. 1995;83:761-71 pubmed
    ..These observations establish the ETS family of DNA-binding proteins as a distinct family of HTH proteins. ..
  12. Mart nez Hackert E, Stock A. The DNA-binding domain of OmpR: crystal structures of a winged helix transcription factor. Structure. 1997;5:109-24 pubmed
    ..The structure of OmpRc could be useful in helping to define the positioning of the alpha subunit of RNA polymerase in relation to transcriptional activators that are bound to DNA...
  13. Buchko G, Litvinova O, Robinson H, Yakunin A, Kennedy M. Functional and structural characterization of DR_0079 from Deinococcus radiodurans, a novel Nudix hydrolase with a preference for cytosine (deoxy)ribonucleoside 5'-Di- and triphosphates. Biochemistry. 2008;47:6571-82 pubmed publisher
  14. Matsutani S. Genetic analyses of the interactions of the IS1-encoded proteins with the left end of IS1 and its insertion hotspot. J Mol Biol. 1997;267:548-60 pubmed
    ..The cis-preference of delta InsA-B'-InsB would result in an overall reduction of transposition of IS1 and its defective copy in a cell, allowing stable existence of the element in its bacterial host. ..
  15. Nair M, McIntosh P, Frenkiel T, Kelly G, Taylor I, Smerdon S, et al. NMR structure of the DNA-binding domain of the cell cycle protein Mbp1 from Saccharomyces cerevisiae. Biochemistry. 2003;42:1266-73 pubmed
    ..The fold-back structure extends the region of positive electrostatic potential, and this may enhance the nonspecific contribution to binding by favorable electrostatic interactions with the DNA backbone. ..
  16. Schumacher S, Clubb R, Cai M, Mizuuchi K, Clore G, Gronenborn A. Solution structure of the Mu end DNA-binding ibeta subdomain of phage Mu transposase: modular DNA recognition by two tethered domains. EMBO J. 1997;16:7532-41 pubmed
    ..Based on the present binding data and the structures of the Ibeta and Igamma subdomains, a model for the interaction of the complete Ibetagamma domain with DNA is proposed. ..
  17. Jain S, Welch J, Horrocks W, Franklin S. Europium luminescence of EF-hand helix-turn-helix chimeras: impact of pH and DNA-binding on europium coordination. Inorg Chem. 2003;42:8098-104 pubmed
    ..The hydration number decreases in the presence of DNA (P3W + DNA, q = 1.9 +/- 0.2; P5b + DNA, q = 1.7 +/- 0.2), indicating that DNA-binding by the metallopeptides organizes rather than compromises the Eu-binding site within the peptide...
  18. Kenney L. Structure/function relationships in OmpR and other winged-helix transcription factors. Curr Opin Microbiol. 2002;5:135-41 pubmed
    ..The current focus of some of the research efforts aimed at understanding activation and DNA binding by response regulators is highlighted in this review. ..
  19. Bieller A, Pasche B, Frank S, Glaser B, Kunz J, Witt K, et al. Isolation and characterization of the human forkhead gene FOXQ1. DNA Cell Biol. 2001;20:555-61 pubmed
    ..The human protein sequence contains two putative transcriptional activation domains, which share a high amino acid identity with the corresponding mouse and rat domains. ..
  20. Perez Rueda E, Collado Vides J. Common history at the origin of the position-function correlation in transcriptional regulators in archaea and bacteria. J Mol Evol. 2001;53:172-9 pubmed
    ..These results suggest that if shuffling of motifs occurred in Bacteria, it occurred only early in the history of these proteins, as opposed to what is observed in eukaryotic regulators. ..
  21. Plumbridge J. Regulation of PTS gene expression by the homologous transcriptional regulators, Mlc and NagC, in Escherichia coli (or how two similar repressors can behave differently). J Mol Microbiol Biotechnol. 2001;3:371-80 pubmed
    ..Displacement of Mlc from its binding sites occurs during growth on glucose and other PTS sugars and involves sequestration of the repressor to membranes by binding to dephosphorylated PtsG. ..
  22. Dou X, Limmer S, Kreutzer R. DNA-binding of phenylalanyl-tRNA synthetase is accompanied by loop formation of the double-stranded DNA. J Mol Biol. 2001;305:451-8 pubmed
  23. Ohta S, Yoshimura E, Ohtsubo E. Involvement of two domains with helix-turn-helix and zinc finger motifs in the binding of IS1 transposase to terminal inverted repeats. Mol Microbiol. 2004;53:193-202 pubmed
  24. Torrents E, Roca I, Gibert I. The open reading frame present in the nrdEF cluster of Corynebacterium ammoniagenes is a transcriptional regulator belonging to the GntR family. Curr Microbiol. 2004;49:152-7 pubmed
    ..The role of this regulator, however, remains unknown. ..
  25. Schwartz T, Rould M, Lowenhaupt K, Herbert A, Rich A. Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA. Science. 1999;284:1841-5 pubmed
    ..A single base contact is observed to guanine in the syn conformation, characteristic of Z-DNA. Intriguingly, the helix-turn-helix motif, frequently used to recognize B-DNA, is used by Zalpha to contact Z-DNA. ..
  26. Eiting M, Hagel ken G, Schubert W, Heinz D. The mutation G145S in PrfA, a key virulence regulator of Listeria monocytogenes, increases DNA-binding affinity by stabilizing the HTH motif. Mol Microbiol. 2005;56:433-46 pubmed publisher
  27. Stegmaier P, Kel A, Wingender E. Systematic DNA-binding domain classification of transcription factors. Genome Inform. 2004;15:276-86 pubmed
    ..The HMM library obtained can be used to classify any newly discovered transcription factor according to its DNA-binding domain and, thus, to generate hypotheses about its DNA-binding specificity. ..
  28. Pritchett M, Wilkinson S, Geiduschek E, Ouhammouch M. Hybrid Ptr2-like activators of archaeal transcription. Mol Microbiol. 2009;74:582-93 pubmed publisher
    ..In contrast, the effector domain of Ptr1, the M. jannaschii Ptr2 paralogue, yields only very weak activation...
  29. Liu Y, Manna A, Pan C, Kriksunov I, Thiel D, Cheung A, et al. Structural and function analyses of the global regulatory protein SarA from Staphylococcus aureus. Proc Natl Acad Sci U S A. 2006;103:2392-7 pubmed
    ..These data suggest that the winged region of the winged helix protein participates in DNA binding and activation, whereas the putative divalent cation binding pocket is only involved in gene function. ..
  30. Kim I, Lee C, Kim M, Kim J, Kim J, Yim H, et al. Crystal structure of the DNA-binding domain of BldD, a central regulator of aerial mycelium formation in Streptomyces coelicolor A3(2). Mol Microbiol. 2006;60:1179-93 pubmed publisher
    ..In addition, structural and mutational investigation reveals that the Tyr62Cys mutation, found in the first-identified bldD mutant, can destabilize BldD structure by disrupting the hydrophobic core...
  31. Kaito C, Morishita D, Matsumoto Y, Kurokawa K, Sekimizu K. Novel DNA binding protein SarZ contributes to virulence in Staphylococcus aureus. Mol Microbiol. 2006;62:1601-17 pubmed publisher
    ..These results suggest that the DNA binding activity of the SarZ protein is required for virulence in S. aureus...
  32. Venanzi M, Gatto E, Bocchinfuso G, Palleschi A, Stella L, Baldini C, et al. Peptide folding dynamics: a time-resolved study from the nanosecond to the microsecond time regime. J Phys Chem B. 2006;110:22834-41 pubmed
  33. Religa T, Johnson C, Vu D, Brewer S, Dyer R, Fersht A. The helix-turn-helix motif as an ultrafast independently folding domain: the pathway of folding of Engrailed homeodomain. Proc Natl Acad Sci U S A. 2007;104:9272-7 pubmed
    ..Experiments on mutated and engineered fragments of the parent protein with different probes allowed the assignment of the observed kinetic phases to specific events to show that EnHD is not an example of one-state downhill folding. ..
  34. Streisfeld M, Rausher M. Relaxed constraint and evolutionary rate variation between basic helix-loop-helix floral anthocyanin regulators in Ipomoea. Mol Biol Evol. 2007;24:2816-26 pubmed
    ..More specifically, they suggest that most of the amino acid substitutions are neutral and do not implicate a role for natural selection on these regulatory genes in the diversification of flower color in Ipomoea...
  35. Kumarevel T, Tanaka T, Nishio M, Gopinath S, Takio K, Shinkai A, et al. Crystal structure of the MarR family regulatory protein, ST1710, from Sulfolobus tokodaii strain 7. J Struct Biol. 2008;161:9-17 pubmed
    ..We also show the protein-DNA interactions by biochemical methods. Our molecular modeling analysis suggested that Asp88 and Arg90 are the key residues in ST1710 involved in the protein-DNA interactions...
  36. Schumacher M, Choi K, Lu F, Zalkin H, Brennan R. Mechanism of corepressor-mediated specific DNA binding by the purine repressor. Cell. 1995;83:147-55 pubmed
  37. Gillette W, Martin R, Rosner J. Probing the Escherichia coli transcriptional activator MarA using alanine-scanning mutagenesis: residues important for DNA binding and activation. J Mol Biol. 2000;299:1245-55 pubmed
    ..Furthermore, the important role of phosphate contacts in marbox affinity suggests that indirect readout contributes to binding site recognition by MarA. ..
  38. Yeagle P, Alderfer J, Albert A. Structure of the third cytoplasmic loop of bovine rhodopsin. Biochemistry. 1995;34:14621-5 pubmed
    ..A model of a turn-helix-turn motif could then be proposed for the third cytoplasmic loop of rhodopsin, which suggested a molecular switch for activation of the G-protein by the receptor. ..
  39. Samuelsson T, Macao B, B lske G. A 13-kDa protein with a helix-turn-helix motif is encoded by bacterial operons related to the SRP pathway. Biochem Biophys Res Commun. 1997;231:839-43 pubmed publisher
    ..Sequence analysis of the p13 proteins strongly suggest that they have a helix-turn-helix (HTH) motif, indicating that they are gene regulatory proteins...
  40. Wootton J. Evaluating the effectiveness of sequence analysis algorithms using measures of relevant information. Comput Chem. 1997;21:191-202 pubmed
    ..The combined use of relevance weights and information measures appears to offer promising advantages over ROC analysis and may be generally applicable to diagnostic evaluation. ..
  41. Lagrange T, Kapanidis A, Tang H, Reinberg D, Ebright R. New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB. Genes Dev. 1998;12:34-44 pubmed
  42. Tan S, Richmond T. Eukaryotic transcription factors. Curr Opin Struct Biol. 1998;8:41-8 pubmed
    ..In addition, recent studies of proximal/distal promoter complexes demonstrate that DNA-binding motifs may be modified in nature by adding secondary structure elements to diversify DNA-binding specificities and affinities. ..
  43. Rho S, Lee J, Jeong E, Kim K, Kim Y, Kim S. A multifunctional repeated motif is present in human bifunctional tRNA synthetase. J Biol Chem. 1998;273:11267-73 pubmed
    ..Results of the present work suggest that the region comprising the repeated motifs of EPRS provides potential sites for interactions with various biological molecules and thus plays diverse roles in the cell. ..
  44. Furui J, Uegaki K, Yamazaki T, Shirakawa M, Swindells M, Harada H, et al. Solution structure of the IRF-2 DNA-binding domain: a novel subgroup of the winged helix-turn-helix family. Structure. 1998;6:491-500 pubmed
    ..The evidence here implies that the evolutional pathway of the IRF family is distinct from that of the other wHTH proteins, in other words, the immune system diverged from an evolutional stem at an early stage. ..
  45. Rupert P, Mollah A, Mossing M, Matthews B. The structural basis for enhanced stability and reduced DNA binding seen in engineered second-generation Cro monomers and dimers. J Mol Biol. 2000;296:1079-90 pubmed
    ..The improved thermal stability is seen to be due to the enhanced solvent transfer free energy of Trp58 relative to Phe58, supplemented in the dimer structure, although not the monomer, by a reduction in volume of internal cavities. ..
  46. Lewis R, Krzywda S, Brannigan J, Turkenburg J, Muchová K, Dodson E, et al. The trans-activation domain of the sporulation response regulator Spo0A revealed by X-ray crystallography. Mol Microbiol. 2000;38:198-212 pubmed
    ..The structural results are discussed in the context of the rich array of existing mutational data. ..
  47. Siegmund T, Lehmann M. The Drosophila Pipsqueak protein defines a new family of helix-turn-helix DNA-binding proteins. Dev Genes Evol. 2002;212:152-7 pubmed
    ..The high sequence conservation of the E93 Psq motif allowed the identification of E93 orthologs in humans and lower metazoans. ..
  48. Blackshear P, Graves J, Stumpo D, Cobos I, Rubenstein J, Zeldin D. Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4. Development. 2003;130:4539-52 pubmed
    ..These findings may be relevant to human congenital hydrocephalus, a birth defect that affects approximately 0.6 per 1000 newborns. ..
  49. Rigali S, Schlicht M, Hoskisson P, Nothaft H, Merzbacher M, Joris B, et al. Extending the classification of bacterial transcription factors beyond the helix-turn-helix motif as an alternative approach to discover new cis/trans relationships. Nucleic Acids Res. 2004;32:3418-26 pubmed publisher
    ..In conclusion, our in silico approach permitted to highlight the specific TF of a regulon out of the 673 orfs annotated as 'regulatory proteins' within the genome of S.coelicolor...
  50. Jeon H, Shin H, Choi J, HOE H, Kim H, Suh S, et al. Mutational analyses of the thermostable NAD+-dependent DNA ligase from Thermus filiformis. FEMS Microbiol Lett. 2004;237:111-8 pubmed
    ..The enzymatic properties of Tfi-M1 mutant (deleted the BRCT domain) were slightly different from those of wild-type and the nick-closing activity of Tfi-M1 mutant was approximately 50% compared with that of wild-type...
  51. Patsialou A, Wilsker D, Moran E. DNA-binding properties of ARID family proteins. Nucleic Acids Res. 2005;33:66-80 pubmed
    ..Most probably, this is determined by multiple interacting differences across the entire ARID structure. ..
  52. Griffin V, McMiller T, Jones E, Johnson C. Identifying novel helix-loop-helix genes in Caenorhabditis elegans through a classroom demonstration of functional genomics. Cell Biol Educ. 2003;2:51-62 pubmed
    ..This article describes the laboratory activity and the assessment of the effectiveness of the activity. ..
  53. Ton Hoang B, Turlan C, Chandler M. Functional domains of the IS1 transposase: analysis in vivo and in vitro. Mol Microbiol. 2004;53:1529-43 pubmed