Summary: Helix-turn-helix domain
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Helix-turn-helix Edit Wikipedia article
In proteins, the helix-turn-helix (HTH) is a major structural motif capable of binding DNA. It is composed of two α helices joined by a short strand of amino acids and is found in many proteins that regulate gene expression. It should not be confused with the helix-loop-helix domain.
The discovery of the helix-turn-helix motif was based on similarities between several genes encoding transcription regulatory proteins from bacteriophage lambda and Escherichia coli: Cro, CAP, and λ repressor, which were found to share a common 20-25 amino acid sequence that facilitates DNA recognition.
The helix-turn-helix motif is a DNA-binding motif. The recognition and binding to DNA by helix-turn-helix proteins is done by the two α helices, one occupying the N-terminal end of the motif, the other at the C-terminus. In most cases, such as in the Cro repressor, the second helix contributes most to DNA recognition, and hence it is often called the "recognition helix". It binds to the major groove of DNA through a series of hydrogen bonds and various Van der Waals interactions with exposed bases. The other α helix stabilizes the interaction between protein and DNA, but does not play a particularly strong role in its recognition.. The recognition helix and its preceding helix always have the same relative orientation.
Classification of helix-turn-helix motifs
The di-helical helix-turn-helix motif is the simplest helix-turn-helix motif. A fragment of Engrailed homeodomain encompassing only the two helices and the turn was found to be an ultrafast independently folding protein domain.
The tetra-helical helix-turn-helix motif has an additional C-terminal helix compared to the tri-helical motifs. These include the LuxR-type DNA-binding HTH domain found in bacterial transcription factors and the helix-turn-helix motif found in the TetR repressors. Multihelical versions with additional helices also occur.
The winged helix-turn-helix (wHTH) motif is formed by a 3-helical bundle and a 3- or 4-strand beta-sheet (wing). The topology of helices and strands in the wHTH motifs may vary. In the transcription factor ETS wHTH folds into a helix-turn-helix motif on a four-stranded anti-parallel beta-sheet scaffold arranged in the order α1-β1-β2-α2-α3-β3-β4 where the third helix is the DNA recognition helix.
Other modified helix-turn-helix motifs
Other derivatives of the helix-turn-helix motif include the DNA-binding domain found in MarR, a regulator of multiple antibiotic resistance, which forms a winged helix-turn-helix with an additional C-terminal alpha helix.
- Brennan RG, Matthews BW (1989). "The helix-turn-helix DNA binding motif.". J Biol Chem 264 (4): 1903–6. PMID 2644244.
- Matthews BW, Ohlendorf DH, Anderson WF, Takeda Y (1982). "Structure of the DNA-binding region of lac repressor inferred from its homology with cro repressor.". Proc Natl Acad Sci U S A 79 (5): 1428–32. doi:10.1073/pnas.79.5.1428. PMC 345986. PMID 6951187.
- Anderson WF, Ohlendorf DH, Takeda Y, Matthews BW (1981). "Structure of the cro repressor from bacteriophage lambda and its interaction with DNA.". Nature 290 (5809): 754–8. doi:10.1038/290754a0. PMID 6452580.
- McKay DB, Steitz TA (1981). "Structure of catabolite gene activator protein at 2.9 A resolution suggests binding to left-handed B-DNA.". Nature 290 (5809): 744–9. doi:10.1038/290744a0. PMID 6261152.
- Pabo CO, Lewis M (1982). "The operator-binding domain of lambda repressor: structure and DNA recognition.". Nature 298 (5873): 443–7. doi:10.1038/298443a0. PMID 7088190.
- Wintjens R, Rooman M (1996). "Structural classification of HTH DNA-binding domains and protein-DNA interaction modes.". J Mol Biol 262 (2): 294–313. doi:10.1006/jmbi.1996.0514. PMID 8831795.
- Suzuki M, Brenner SE (1995). "Classification of multi-helical DNA-binding domains and application to predict the DBD structures of sigma factor, LysR, OmpR/PhoB, CENP-B, Rapl, and Xy1S/Ada/AraC.". FEBS Lett 372 (2-3): 215–21. doi:10.1016/0014-5793(95)00988-L. PMID 7556672.
- Aravind L, Anantharaman V, Balaji S, Babu MM, Iyer LM (2005). "The many faces of the helix-turn-helix domain: transcription regulation and beyond.". FEMS Microbiol Rev 29 (2): 231–62. doi:10.1016/j.femsre.2004.12.008. PMID 15808743.
- Religa TL, Johnson CM, Vu DM, Brewer SH, Dyer RB, Fersht AR (2007). "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 104 (22): 9272–9277. doi:10.1073/pnas.0703434104. PMID 17517666.
- Ogata K, Hojo H, Aimoto S, Nakai T, Nakamura H, Sarai A et al. (1992). "Solution structure of a DNA-binding unit of Myb: a helix-turn-helix-related motif with conserved tryptophans forming a hydrophobic core.". Proc Natl Acad Sci U S A 89 (14): 6428–32. doi:10.1073/pnas.89.14.6428. PMC 49514. PMID 1631139.
- Hinrichs W, Kisker C, Düvel M, Müller A, Tovar K, Hillen W et al. (1994). "Structure of the Tet repressor-tetracycline complex and regulation of antibiotic resistance.". Science 264 (5157): 418–20. doi:10.1126/science.8153629. PMID 8153629.
- Iwahara J, Clubb RT (1999). "Solution structure of the DNA binding domain from Dead ringer, a sequence-specific AT-rich interaction domain (ARID).". EMBO J 18 (21): 6084–94. doi:10.1093/emboj/18.21.6084. PMC 1171673. PMID 10545119.
- Donaldson LW, Petersen JM, Graves BJ, McIntosh LP (1996). "Solution structure of the ETS domain from murine Ets-1: a winged helix-turn-helix DNA binding motif". EMBO J. 15 (1): 125–34. PMC 449924. PMID 8598195.
- Sharrocks AD, Brown AL, Ling Y, Yates PR (1997). "The ETS-domain transcription factor family". Int. J. Biochem. Cell Biol. 29 (12): 1371–87. doi:10.1016/S1357-2725(97)00086-1. PMID 9570133.
- Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF (2001). "The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 A resolution.". Nat Struct Biol 8 (8): 710–4. doi:10.1038/90429. PMID 11473263.
- Struhl K (1989). "Helix-turn-helix, zinc-finger, and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins.". Trends Biochem Sci 14 (4): 137–40. doi:10.1016/0968-0004(89)90145-X. PMID 2499084.
- Gajiwala KS, Burley SK (2000). "Winged helix proteins.". Curr Opin Struct Biol 10 (1): 110–6. PMID 10679470.
- Santos CL, Tavares F, Thioulouse J, Normand P (2009). "A phylogenomic analysis of bacterial helix-turn-helix transcription factors.". FEMS Microbiol Rev 33 (2): 411–29. doi:10.1111/j.1574-6976.2008.00154.x. PMID 19076237.
- Hoskisson PA, Rigali S (2009). "Chapter 1: Variation in form and function the helix-turn-helix regulators of the GntR superfamily.". Adv Appl Microbiol 69: 1–22. doi:10.1016/S0065-2164(09)69001-8. PMID 19729089.
- Brennan RG (1993). "The winged-helix DNA-binding motif: another helix-turn-helix takeoff.". Cell 74 (5): 773–6. doi:10.1016/0092-8674(93)90456-Z. PMID 8374950.
- Huffman JL, Brennan RG (2002). "Prokaryotic transcription regulators: more than just the helix-turn-helix motif.". Curr Opin Struct Biol 12 (1): 98–106. PMID 11839496.
- Helix-turn-helix motif, lambda-like repressor, from EMBL
- Full PDB entry for PDB ID 1LMB
- Cro/C1-type HTH domain, more HTHs in PROSITE
|Pfam infoboxes for Helix-turn-helix domains|
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|Similarity to PfamA using HHSearch:||HTH_AraC HTH_AraC|
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This family contains a diverse range of mostly DNA-binding domains that contain a helix-turn-helix motif.
The clan contains the following 202 members:AphA_like Arg_repressor B-block_TFIIIC Bac_DnaA_C BetR Bot1p BrkDBD CENP-B_N Cro Crp DDRGK Dimerisation DUF1133 DUF1153 DUF1323 DUF134 DUF1441 DUF1492 DUF1495 DUF1670 DUF1804 DUF1836 DUF1870 DUF2089 DUF2250 DUF2316 DUF3116 DUF3853 DUF387 DUF3908 DUF4095 DUF4364 DUF739 DUF742 DUF977 E2F_TDP ELK Ets Exc F-112 FaeA Fe_dep_repr_C Fe_dep_repress FeoC Ftsk_gamma FUR GcrA GerE GntR HARE-HTH HemN_C Homeobox Homeobox_KN Homez HrcA_DNA-bdg HSF_DNA-bind HTH_1 HTH_10 HTH_11 HTH_12 HTH_13 HTH_15 HTH_16 HTH_17 HTH_18 HTH_19 HTH_20 HTH_21 HTH_22 HTH_23 HTH_24 HTH_25 HTH_26 HTH_27 HTH_28 HTH_29 HTH_3 HTH_30 HTH_31 HTH_32 HTH_33 HTH_34 HTH_35 HTH_36 HTH_37 HTH_38 HTH_39 HTH_40 HTH_41 HTH_42 HTH_43 HTH_45 HTH_5 HTH_6 HTH_7 HTH_8 HTH_9 HTH_AraC HTH_AsnC-type HTH_CodY HTH_Crp_2 HTH_DeoR HTH_IclR HTH_Mga HTH_OrfB_IS605 HTH_psq HTH_Tnp_1 HTH_Tnp_1_2 HTH_Tnp_4 HTH_Tnp_IS1 HTH_Tnp_IS630 HTH_Tnp_ISL3 HTH_Tnp_Mu_1 HTH_Tnp_Mu_2 HTH_Tnp_Tc3_1 HTH_Tnp_Tc3_2 HTH_Tnp_Tc5 HTH_WhiA HxlR IF2_N KorB LacI LexA_DNA_bind LZ_Tnp_IS481 MADF_DNA_bdg MarR MarR_2 Med9 MerR MerR-DNA-bind MerR_1 MerR_2 Mga Mnd1 Mor MotA_activ MRP-L20 Myb_DNA-bind_2 Myb_DNA-bind_3 Myb_DNA-bind_4 Myb_DNA-bind_5 Myb_DNA-bind_6 Myb_DNA-binding Neugrin NUMOD1 OST-HTH P22_Cro PaaX PadR PAX PCI PCI_Csn8 Penicillinase_R Phage_AlpA Phage_antitermQ Phage_CI_repr Phage_CII Phage_rep_org_N Phage_terminase Pou Pox_D5 PuR_N Put_DNA-bind_N Rap1-DNA-bind Rep_3 RepA_C RepA_N RepC RepL Replic_Relax RFX_DNA_binding Ribosomal_S25 Rio2_N RNA_pol_Rpc34 RP-C RPA RPA_C RQC Rrf2 RTP SAC3_GANP SgrR_N Sigma54_CBD Sigma54_DBD Sigma70_ECF Sigma70_r2 Sigma70_r3 Sigma70_r4 Sigma70_r4_2 SpoIIID Sulfolobus_pRN TBPIP Terminase_5 TetR_N TFIIE_alpha Tn916-Xis Trans_reg_C TrfA TrmB Trp_repressor UPF0122 z-alpha
We make a range of alignments for each Pfam-A family:
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Curation and family details
|Number in seed:||512|
|Number in full:||57814|
|Average length of the domain:||79.60 aa|
|Average identity of full alignment:||26 %|
|Average coverage of the sequence by the domain:||23.35 %|
|HMM build commands:||
build method: hmmbuild --amino -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||2|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HTH_18 domain has been found. There are 19 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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