Protein-DNA interactions: amino acid conservation and the effects of mutations on binding specificity.
We investigate the conservation of amino acid residue sequences in 21 DNA-binding protein families and study the effects that mutations have on DNA-sequence recognition. The observations are best understood by assigning each protein family to one of three classes: (i) non-specific, where binding is independent of DNA sequence; (ii) highly specific, where binding is specific and all members of the family target the same DNA sequence; and (iii) multi-specific, where binding is also specific, but individual family members target different DNA sequences. Overall, protein residues in contact with the DNA are better conserved than the rest of the protein surface, but there is a complex underlying trend of conservation for individual residue positions. Amino acid residues that interact with the DNA backbone are well conserved across all protein families and provide a core of stabilising contacts for homologous protein-DNA complexes. In contrast, amino acid residues that interact with DNA bases have variable levels of conservation depending on the family classification. In non-specific families, base-contacting residues are well conserved and interactions are always found in the minor groove where there is little discrimination between base types. In highly specific families, base-contacting residues are highly conserved and allow member proteins to recognise the same target sequence. In multi-specific families, base-contacting residues undergo frequent mutations and enable different proteins to recognise distinct target sequences. Finally, we report that interactions with bases in the target sequence often follow (though not always) a universal code of amino acid-base recognition and the effects of amino acid mutations can be most easily understood for these interactions.
Luscombe
Nicholas M
NM
Biomolecular Structures and Modelling Unit, Department of Biochemistry and Molecular Biology, University College, London, UK. nicholas.luscombe@yale.edu
Thornton
Janet M
JM
D000595:Amino Acid Sequence; D000596:Amino Acids; D001665:Binding Sites; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
D000596:Amino Acids; D004268:DNA-Binding Proteins; D004247:DNA