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The role of DNA shape in protein–DNA recognition

Abstract

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.

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Figure 1: Amino acid frequencies in minor grooves.
Figure 2: Distribution of tetranucleotide sequences according to average minor-groove width.
Figure 3: Specific examples of minor-groove shape recognition by arginines.
Figure 4: Minor-groove shape recognition in the nucleosome.
Figure 5: The biophysical origins of the negative potential of narrow minor grooves.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants GM54510 (R.S.M.) and U54 CA121852 (B.H. and R.S.M.). The authors thank A. Califano for many helpful conversations.

Author Contributions R.R., A.S., R.S.M. and B.H. contributed to the original conception of the project; S.M.W. and R.R. generated and analysed the data assisted by P.L.; and R.R., S.M.W., R.S.M. and B.H. wrote the manuscript.

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Correspondence to Richard S. Mann or Barry Honig.

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Rohs, R., West, S., Sosinsky, A. et al. The role of DNA shape in protein–DNA recognition. Nature 461, 1248–1253 (2009). https://doi.org/10.1038/nature08473

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