Helix-turn-helix explained

Symbol:	HTH
Helix-turn-helix
Pfam Clan:	CL0123

Helix-turn-helix is a DNA-binding domain (DBD). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two α helices, joined by a short strand of amino acids, that bind to the major groove of DNA. The HTH motif occurs in many proteins that regulate gene expression. It should not be confused with the helix–loop–helix motif.^[1]

Discovery

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.^{[2] [3] [4] [5]}

Function

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.^[6]

Classification of helix-turn-helix motifs

Several attempts have been made to classify the helix-turn-helix motifs based on their structure and the spatial arrangement of their helices.^{[7] [8]} Some of the main types are described below.

Di-helical

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.^[9]

Tri-helical

An example of this motif is found in the transcriptional activator Myb.^[10]

Tetra-helical

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.^[11] Multihelical versions with additional helices also occur.^[12]

Winged helix-turn-helix

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.^{[13] [14]}

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.^[15]

See also

• DNA-binding domain
• DNA-binding protein
• Secondary structure
• Zinc finger

Further reading

• Struhl K . Helix-turn-helix, zinc-finger, and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins . Trends in Biochemical Sciences . 14 . 4 . 137–40 . April 1989 . 2499084 . 10.1016/0968-0004(89)90145-X .
• Gajiwala KS, Burley SK . Winged helix proteins . Current Opinion in Structural Biology . 10 . 1 . 110–6 . February 2000 . 10679470 . 10.1016/S0959-440X(99)00057-3.
• Santos CL, Tavares F, Thioulouse J, Normand P . A phylogenomic analysis of bacterial helix-turn-helix transcription factors . FEMS Microbiology Reviews . 33 . 2 . 411–29 . March 2009 . 19076237 . 10.1111/j.1574-6976.2008.00154.x . free .
• Hoskisson PA, Rigali S . Chapter 1: Variation in form and function the helix-turn-helix regulators of the GntR superfamily . Advances in Applied Microbiology . 69 . 1–22 . 2009 . 19729089 . 10.1016/S0065-2164(09)69001-8 .
• Brennan RG . The winged-helix DNA-binding motif: another helix-turn-helix takeoff . Cell . 74 . 5 . 773–6 . September 1993 . 8374950 . 10.1016/0092-8674(93)90456-Z . 31355349 .
• Huffman JL, Brennan RG . Prokaryotic transcription regulators: more than just the helix-turn-helix motif . Current Opinion in Structural Biology . 12 . 1 . 98–106 . February 2002 . 11839496 . 10.1016/s0959-440x(02)00295-6 .

External links

• 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

Notes and References

1. Brennan RG, Matthews BW . The helix-turn-helix DNA binding motif . The Journal of Biological Chemistry . 264 . 4 . 1903–6 . February 1989 . 10.1016/S0021-9258(18)94115-3 . 2644244 . free .
2. Matthews BW, Ohlendorf DH, Anderson WF, Takeda Y . Structure of the DNA-binding region of lac repressor inferred from its homology with cro repressor . Proceedings of the National Academy of Sciences of the United States of America . 79 . 5 . 1428–32 . March 1982 . 6951187 . 345986 . 10.1073/pnas.79.5.1428 . 1982PNAS...79.1428M . free .
3. Anderson WF, Ohlendorf DH, Takeda Y, Matthews BW . Structure of the cro repressor from bacteriophage lambda and its interaction with DNA . Nature . 290 . 5809 . 754–8 . April 1981 . 6452580 . 10.1038/290754a0 . 1981Natur.290..754A . 4360799 .
4. McKay DB, Steitz TA . Structure of catabolite gene activator protein at 2.9 A resolution suggests binding to left-handed B-DNA . Nature . 290 . 5809 . 744–9 . April 1981 . 6261152 . 10.1038/290744a0 . 1981Natur.290..744M . 568056 .
5. Pabo CO, Lewis M . The operator-binding domain of lambda repressor: structure and DNA recognition . Nature . 298 . 5873 . 443–7 . July 1982 . 7088190 . 10.1038/298443a0 . 1982Natur.298..443P . 39169630 .
6. Wintjens R, Rooman M . Structural classification of HTH DNA-binding domains and protein-DNA interaction modes . Journal of Molecular Biology . 262 . 2 . 294–313 . September 1996 . 8831795 . 10.1006/jmbi.1996.0514 .
7. Suzuki M, Brenner SE . 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 Letters . 372 . 2–3 . 215–21 . September 1995 . 7556672 . 10.1016/0014-5793(95)00988-L . 3037519 . 1995FEBSL.372..215S .
8. Aravind L, Anantharaman V, Balaji S, Babu MM, Iyer LM . The many faces of the helix-turn-helix domain: transcription regulation and beyond . FEMS Microbiology Reviews . 29 . 2 . 231–62 . April 2005 . 15808743 . 10.1016/j.femsre.2004.12.008 . 2024-04-26 .
9. Religa TL, Johnson CM, Vu DM, Brewer SH, Dyer RB, Fersht AR . The helix-turn-helix motif as an ultrafast independently folding domain: the pathway of folding of Engrailed homeodomain . Proceedings of the National Academy of Sciences of the United States of America . 104 . 22 . 9272–7 . May 2007 . 17517666 . 1890484 . 10.1073/pnas.0703434104 . 2007PNAS..104.9272R . free .
10. Ogata K, Hojo H, Aimoto S, Nakai T, Nakamura H, Sarai A, Ishii S, Nishimura Y . Solution structure of a DNA-binding unit of Myb: a helix-turn-helix-related motif with conserved tryptophans forming a hydrophobic core . Proceedings of the National Academy of Sciences of the United States of America . 89 . 14 . 6428–32 . July 1992 . 1631139 . 49514 . 10.1073/pnas.89.14.6428 . 1992PNAS...89.6428O . free .
11. Hinrichs W, Kisker C, Düvel M, Müller A, Tovar K, Hillen W, Saenger W . Structure of the Tet repressor-tetracycline complex and regulation of antibiotic resistance . Science . 264 . 5157 . 418–20 . April 1994 . 8153629 . 10.1126/science.8153629 . 1994Sci...264..418H .
12. Iwahara J, Clubb RT . Solution structure of the DNA binding domain from Dead ringer, a sequence-specific AT-rich interaction domain (ARID) . The EMBO Journal . 18 . 21 . 6084–94 . November 1999 . 10545119 . 1171673 . 10.1093/emboj/18.21.6084 .
13. Donaldson LW, Petersen JM, Graves BJ, McIntosh LP . Solution structure of the ETS domain from murine Ets-1: a winged helix-turn-helix DNA binding motif . The EMBO Journal . 15 . 1 . 125–34 . January 1996 . 8598195 . 449924 . 10.2210/pdb1etc/pdb .
14. Sharrocks AD, Brown AL, Ling Y, Yates PR . The ETS-domain transcription factor family . The International Journal of Biochemistry & Cell Biology . 29 . 12 . 1371–87 . December 1997 . 9570133 . 10.1016/S1357-2725(97)00086-1 .
15. Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF . The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 A resolution . Nature Structural Biology . 8 . 8 . 710–4 . August 2001 . 11473263 . 10.1038/90429 . 19608515 .