Functional Ambidexterity of an Ancient Nucleic Acid-Binding Domain.

ABSTRACT: The helix-hairpin-helix (HhH) motif is an ancient and ubiquitous nucleic acid-binding element that has emerged as a model system for studying the evolution of dsDNA-binding domains from simple peptides that phase separate with RNA. We analyzed the entire putative evolutionary trajectory of the HhH motif - from a flexible peptide to a folded domain - for functional robustness to total chiral inversion. Against expectations, functional "ambidexterity" was observed for both the phase separation of HhH peptides with RNA and binding of the duplicated (HhH)₂-Fold to dsDNA. Moreover, dissociation kinetics, mutational analysis, and molecular dynamics simulations revealed an overlap between the binding modes adopted by the natural and mirror-image proteins to natural dsDNA. The similarit

SUBMITTER: Weil-Ktorza O 

PROVIDER: S-EPMC12171331 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature