The role of DNA shape in protein–DNA recognition

The recognition of specific DNA sequences by proteins is thought to depend on two types of mechanism: one that involves the formation of hydrogen bonds with specific bases, primarily in the major groove, and one involving sequence-dependent deformations of the DNA helix. By comprehensively analysing the three-dimensional structures of protein–DNA complexes, here we show that the binding of arginine residues to narrow minor grooves is a widely used mode for protein–DNA recognition. This readout mechanism exploits the phenomenon that narrow minor grooves strongly enhance the negative electrostatic potential of the DNA. The nucleosome core particle offers a prominent example of this effect. Minor-groove narrowing is often associated with the presence of A-tracts, AT-rich sequences that exclude the flexible TpA step. These findings indicate that the ability to detect local variations in DNA shape and electrostatic potential is a general mechanism that enables proteins to use information in the minor groove, which otherwise offers few opportunities for the formation of base-specific hydrogen bonds, to achieve DNA-binding specificity. Major to minor How sequence-specific DNA-binding proteins can find targets in the midst of vast amounts of non-specific DNA is a long-standing puzzle. A favoured model was that the sequence was read as hydrogen bonds formed between the protein and bases in the major groove of the DNA helix. A new analysis of the three-dimensional structures of protein–DNA complexes suggests that DNA shape is key to recognition. DNA sequence context alters the width of the minor groove of the helix by preferential binding of arginines to electronegative pockets. The positioning of DNA in the nucleosome core particle is an example of this effect. The question of how proteins recognize specific DNA sequences in the face of vastly higher concentrations of non-specific DNA remains unclear. One suggested mechanism involves the formation of hydrogen bonds with specific bases, primarily in the major groove. The comprehensive analysis of the three-dimensional structures of protein–DNA complexes now shows that the binding of arginine residues to narrow minor grooves is a widely used mode for protein–DNA recognition.