Molecular evolution of helix-turn-helix proteins

The helix-turn-helix domain-containing family of transcriptional regulators is of ancient origin and has been incorporated into numerous disparate bio logical processes. As a consequence, the forces shaping its early evolution have been difficult to reconstruct. Herein, we analyze this large and dive rse family with a combination of traditional phylogenetic techniques and ne wer sequence analysis tools to determine whether the helix-turn-helix famil y arose from a single common ancestor. Our analyses of the DNA-binding doma in show that amino acid chemistry is conserved at many sites in the first h elix and the turn. The high level of divergence combined with the short len gth of the domain hinders robust reconstruction of the entire phylogeny, bu t some level of deep node inference is possible. All analyses point to a pr edominantly monophyletic origin for the helix-turn-helix domain. The conseq uences of such an origin for a diverse group of proteins, and guidelines fo r the identification of future members of the HTH family are discussed.