Common fold in helix-hairpin-helix proteins.
Helix-hairpin-helix (HhH) is a widespread motif involved in non-sequence-specific DNA binding. The majority of HhH motifs function as DNA-binding modules, however, some of them are used to mediate protein-protein interactions or have acquired enzymatic activity by incorporating catalytic residues (DNA glycosylases). From sequence and structural analysis of HhH-containing proteins we conclude that most HhH motifs are integrated as a part of a five-helical domain, termed (HhH)(2) domain here. It typically consists of two consecutive HhH motifs that are linked by a connector helix and displays pseudo-2-fold symmetry. (HhH)(2) domains show clear structural integrity and a conserved hydrophobic core composed of seven residues, one residue from each alpha-helix and each hairpin, and deserves recognition as a distinct protein fold. In addition to known HhH in the structures of RuvA, RadA, MutY and DNA-polymerases, we have detected new HhH motifs in sterile alpha motif and barrier-to-autointegration factor domains, the alpha-subunit of Escherichia coli RNA-polymerase, DNA-helicase PcrA and DNA glycosylases. Statistically significant sequence similarity of HhH motifs and pronounced structural conservation argue for homology between (HhH)(2) domains in different protein families. Our analysis helps to clarify how non-symmetric protein motifs bind to the double helix of DNA through the formation of a pseudo-2-fold symmetric (HhH)(2) functional unit.
Shao
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Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.
Grishin
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D000595:Amino Acid Sequence; D002675:Child, Preschool; D045647:DNA Glycosylases; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics; D019951:DNA Polymerase beta / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry / Q000235:genetics; D029968:Escherichia coli Proteins; D005092:Exonucleases / Q000737:chemistry / Q000235:genetics; D019077:Helix-Turn-Helix Motifs / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D012321:DNA-Directed RNA Polymerases; C113275:RNA polymerase alpha subunit; D019951:DNA Polymerase beta; D005092:Exonucleases; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C071059:Holliday junction DNA helicase, E coli; D004265:DNA Helicases