The λ repressor ofbacteriophage lambda employs two helix-turn-helix motifs (left; green) to bindDNA (right; blue and red). The λ repressor protein in this image is adimer.
Helix-turn-helix is aDNA-binding domain (DBD). Thehelix-turn-helix (HTH) is a majorstructural motif capable of bindingDNA. Each monomer incorporates twoα helices, joined by a short strand ofamino acids, that bind to the major groove of DNA. The HTH motif occurs in many proteins that regulategene expression. It should not be confused with thehelix–loop–helix motif.[1]
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 theN-terminal end of the motif, the other at theC-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 ofhydrogen bonds and variousVan der Waals interactions with exposedbases. The other α helix stabilizes the interaction between protein and DNA, but does not play a particularly strong role in its recognition.[2] The recognition helix and its preceding helix always have the same relative orientation.[6]
Several attempts have been made to classify the helix-turn-helix motifs based on their structure and the spatial arrangement of their helices.[6][7][8] Some of the main types are described below.
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]
The tetra-helical helix-turn-helix motif has an additionalC-terminal helix compared to the tri-helical motifs. These include theLuxR-type DNA-binding HTH domain found inbacterial transcription factors and the helix-turn-helix motif found in theTetR repressors.[11] Multihelical versions with additional helices also occur.[12]
The winged helix-turn-helix (wHTH) motif is formed by a 3-helical bundle and a 3- or 4-strandbeta-sheet (wing). The topology ofhelices andstrands in the wHTH motifs may vary. In thetranscription factor ETS wHTH folds into a helix-turn-helix motif on a four-stranded anti-parallelbeta-sheet scaffold arranged in the order α1-β1-β2-α2-α3-β3-β4 where the third helix is the DNA recognitionhelix.[13][14]
Other derivatives of the helix-turn-helix motif include the DNA-binding domain found inMarR, a regulator ofmultiple antibiotic resistance, which forms a winged helix-turn-helix with an additional C-terminal alpha helix.[8][15]
^abWintjens 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.PMID8831795.
^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.PMID8153629.
^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.PMID9570133.
^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.PMID11473263.S2CID19608515.
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.PMID2499084.
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.hdl:2268/25857.PMID19729089.
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.PMID11839496.
