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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.

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.

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.

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. 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.

Tri-helical

An example of this motif is found in the transcriptional activator Myb.

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. Multihelical versions with additional helices also occur.

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.

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.

See also

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

References

1. Brennan RG, Matthews BW (February 1989). "The helix-turn-helix DNA binding motif". The Journal of Biological Chemistry. 264 (4): 1903–6. doi:10.1016/S0021-9258(18)94115-3. PMID 2644244.
2. ^ Matthews BW, Ohlendorf DH, Anderson WF, Takeda Y (March 1982). "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. Bibcode:1982PNAS...79.1428M. doi:10.1073/pnas.79.5.1428. PMC 345986. PMID 6951187.
3. Anderson WF, Ohlendorf DH, Takeda Y, Matthews BW (April 1981). "Structure of the cro repressor from bacteriophage lambda and its interaction with DNA". Nature. 290 (5809): 754–8. Bibcode:1981Natur.290..754A. doi:10.1038/290754a0. PMID 6452580. S2CID 4360799.
4. McKay DB, Steitz TA (April 1981). "Structure of catabolite gene activator protein at 2.9 A resolution suggests binding to left-handed B-DNA". Nature. 290 (5809): 744–9. Bibcode:1981Natur.290..744M. doi:10.1038/290744a0. PMID 6261152. S2CID 568056.
5. Pabo CO, Lewis M (July 1982). "The operator-binding domain of lambda repressor: structure and DNA recognition". Nature. 298 (5873): 443–7. Bibcode:1982Natur.298..443P. doi:10.1038/298443a0. PMID 7088190. S2CID 39169630.
6. ^ Wintjens R, Rooman M (September 1996). "Structural classification of HTH DNA-binding domains and protein-DNA interaction modes". Journal of Molecular Biology. 262 (2): 294–313. doi:10.1006/jmbi.1996.0514. PMID 8831795.
7. Suzuki M, Brenner SE (September 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 Letters. 372 (2–3): 215–21. Bibcode:1995FEBSL.372..215S. doi:10.1016/0014-5793(95)00988-L. PMID 7556672. S2CID 3037519.
8. ^ Aravind L, Anantharaman V, Balaji S, Babu MM, Iyer LM (April 2005). "The many faces of the helix-turn-helix domain: transcription regulation and beyond". FEMS Microbiology Reviews. 29 (2): 231–62. doi:10.1016/j.femsre.2004.12.008. PMID 15808743.
9. Religa TL, Johnson CM, Vu DM, Brewer SH, Dyer RB, Fersht AR (May 2007). "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. Bibcode:2007PNAS..104.9272R. doi:10.1073/pnas.0703434104. PMC 1890484. PMID 17517666.
10. Ogata K, Hojo H, Aimoto S, Nakai T, Nakamura H, Sarai A, Ishii S, Nishimura Y (July 1992). "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. Bibcode:1992PNAS...89.6428O. doi:10.1073/pnas.89.14.6428. PMC 49514. PMID 1631139.
11. Hinrichs W, Kisker C, Düvel M, Müller A, Tovar K, Hillen W, Saenger W (April 1994). "Structure of the Tet repressor-tetracycline complex and regulation of antibiotic resistance". Science. 264 (5157): 418–20. Bibcode:1994Sci...264..418H. doi:10.1126/science.8153629. PMID 8153629.
12. Iwahara J, Clubb RT (November 1999). "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. doi:10.1093/emboj/18.21.6084. PMC 1171673. PMID 10545119.
13. Donaldson LW, Petersen JM, Graves BJ, McIntosh LP (January 1996). "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. doi:10.2210/pdb1etc/pdb. PMC 449924. PMID 8598195.
14. Sharrocks AD, Brown AL, Ling Y, Yates PR (December 1997). "The ETS-domain transcription factor family". The International Journal of Biochemistry & Cell Biology. 29 (12): 1371–87. doi:10.1016/S1357-2725(97)00086-1. PMID 9570133.
15. Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF (August 2001). "The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 A resolution". Nature Structural Biology. 8 (8): 710–4. doi:10.1038/90429. PMID 11473263. S2CID 19608515.

Further reading

• Struhl K (April 1989). "Helix-turn-helix, zinc-finger, and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins". Trends in Biochemical Sciences. 14 (4): 137–40. doi:10.1016/0968-0004(89)90145-X. PMID 2499084.
• Gajiwala KS, Burley SK (February 2000). "Winged helix proteins". Current Opinion in Structural Biology. 10 (1): 110–6. doi:10.1016/S0959-440X(99)00057-3. PMID 10679470.
• Santos CL, Tavares F, Thioulouse J, Normand P (March 2009). "A phylogenomic analysis of bacterial helix-turn-helix transcription factors". FEMS Microbiology Reviews. 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". Advances in Applied Microbiology. 69: 1–22. doi:10.1016/S0065-2164(09)69001-8. PMID 19729089.
• Brennan RG (September 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. S2CID 31355349.
• Huffman JL, Brennan RG (February 2002). "Prokaryotic transcription regulators: more than just the helix-turn-helix motif". Current Opinion in Structural Biology. 12 (1): 98–106. doi:10.1016/s0959-440x(02)00295-6. PMID 11839496.

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

• Protein structural motifs
• Transcription factors
• DNA-binding substances
• Protein domains
• Protein superfamilies