From keys to bulldozers: expanding roles for winged helix domains in nucleic-acid-binding proteins

• The winged helix domain is a versatile nucleic-acid-binding structural element.
• This domain can exploit various nucleic acid structural features for recognition.
• Transcription factors use this domain for sequence-specific DNA recognition.
• DNA recombination and repair helicases use this domain as a strand-separating wedge.
• Winged helix domains also mediate protein–protein interactions.

The winged helix domain (WHD) is a widespread nucleic-acid-binding protein structural element found in all kingdoms of life. Although the overall structure of the WHD is conserved, its functional properties and interaction profiles are extremely versatile. WHD-containing proteins can exploit nearly the full spectrum of nucleic acid structural features for recognition and even covalent modification or noncovalent rearrangement of target molecules. WHD functions range from sequence-recognizing keys in transcription factors and bulldozer-like strand-separating wedges in helicases to mediators of protein–protein interactions (PPIs). Further investigations are needed to understand the contribution of WHD structural dynamics to nucleic-acid-modifying enzymatic functions.