Helixturnhelix

Helix-turn-helix (HTH) is a common DNA-binding motif found in many transcription factors across bacteria and archaea, and in some eukaryotic proteins. The motif comprises two α helices connected by a short turn. The second helix, known as the recognition helix, fits into the major groove of DNA and makes sequence-specific contacts, while the first helix helps stabilize the overall fold.

Typically the core of the motif spans about 20 amino acids. The turn between the helices is usually 3–4 residues long. Many HTH proteins function as dimers or higher-order oligomers, enabling recognition of palindromic or inverted DNA sequences.

Variants include the classic basic HTH and the winged-HTH, in which a small beta-sheet “wing” follows the recognition helix and contributes to DNA contacts. The HTH motif is often found in tandem with additional DNA-binding elements, giving rise to diverse families such as LacI/GalR-type repressors and AraC-family regulators.

Biological role and mechanism: HTH-containing proteins bind specific DNA sequences to regulate transcription. Specificity is determined by residues in the recognition helix and, in some proteins, by partner domains or cofactors. Evolution has diversified the motif into multiple families with differences in helix length, angle, and dimerization mode, allowing a wide range of regulatory controls.

Applications: HTH motifs are used in structural biology and protein engineering to design DNA-binding proteins and study DNA recognition. Motif-based analyses aid in predicting transcription factors in newly sequenced genomes and in guiding synthetic biology approaches.

See also: homeobox domain; winged-helix-turn-helix; zinc finger.