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The role of DNA shape in protein–DNA recognition

Nature volume 461, pages 1248–1253 (2009)Cite this article

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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References

  1. Garvie, C. W. & Wolberger, C. Recognition of specific DNA sequences. Mol. Cell 8, 937–946 (2001)

    Article  CAS  Google Scholar 

  2. Seeman, N. C., Rosenberg, J. M. & Rich, A. Sequence-specific recognition of double helical nucleic acids by proteins. Proc. Natl Acad. Sci. USA 73, 804–808 (1976)

    Article  CAS  ADS  Google Scholar 

  3. Travers, A. A. DNA conformation and protein binding. Annu. Rev. Biochem. 58, 427–452 (1989)

    Article  CAS  Google Scholar 

  4. Shakked, Z. et al. Determinants of repressor/operator recognition from the structure of the trp operator binding site. Nature 368, 469–473 (1994)

    Article  CAS  ADS  Google Scholar 

  5. Lu, X. J., Shakked, Z. & Olson, W. K. A-form conformational motifs in ligand-bound DNA structures. J. Mol. Biol. 300, 819–840 (2000)

    Article  CAS  Google Scholar 

  6. Hegde, R. S., Grossman, S. R., Laimins, L. A. & Sigler, P. B. Crystal structure at 1.7 Å of the bovine papillomavirus-1 E2 DNA-binding domain bound to its DNA target. Nature 359, 505–512 (1992)

    Article  CAS  ADS  Google Scholar 

  7. Kim, Y., Geiger, J. H., Hahn, S. & Sigler, P. B. Crystal structure of a yeast TBP/TATA-box complex. Nature 365, 512–520 (1993)

    Article  CAS  ADS  Google Scholar 

  8. Kim, J. L., Nikolov, D. B. & Burley, S. K. Co-crystal structure of TBP recognizing the minor groove of a TATA element. Nature 365, 520–527 (1993)

    Article  CAS  ADS  Google Scholar 

  9. Otwinowski, Z. et al. Crystal structure of trp repressor/operator complex at atomic resolution. Nature 335, 321–329 (1988)

    Article  CAS  ADS  Google Scholar 

  10. Hizver, J., Rozenberg, H., Frolow, F., Rabinovich, D. & Shakked, Z. DNA bending by an adenine–thymine tract and its role in gene regulation. Proc. Natl Acad. Sci. USA 98, 8490–8495 (2001)

    Article  CAS  ADS  Google Scholar 

  11. Rohs, R., Sklenar, H. & Shakked, Z. Structural and energetic origins of sequence-specific DNA bending: Monte Carlo simulations of papillomavirus E2-DNA binding sites. Structure 13, 1499–1509 (2005)

    Article  CAS  Google Scholar 

  12. Joshi, R. et al. Functional specificity of a Hox protein mediated by the recognition of minor groove structure. Cell 131, 530–543 (2007)

    Article  CAS  Google Scholar 

  13. Burkhoff, A. M. & Tullius, T. D. Structural details of an adenine tract that does not cause DNA to bend. Nature 331, 455–457 (1988)

    Article  CAS  ADS  Google Scholar 

  14. Haran, T. E. & Mohanty, U. The unique structure of A-tracts and intrinsic DNA bending. Q. Rev. Biophys. 42, 41–81 (2009)

    Article  CAS  Google Scholar 

  15. Crothers, D. M. & Shakked, Z. in Oxford Handbook of Nucleic Acid Structures (ed. Neidle, S.) 455–470 (Oxford Univ. Press, 1999)

    Google Scholar 

  16. Passner, J. M., Ryoo, H. D., Shen, L., Mann, R. S. & Aggarwal, A. K. Structure of a DNA-bound Ultrabithorax–Extradenticle homeodomain complex. Nature 397, 714–719 (1999)

    Article  CAS  ADS  Google Scholar 

  17. Li, T., Jin, Y., Vershon, A. K. & Wolberger, C. Crystal structure of the MATa1/MATα2 homeodomain heterodimer in complex with DNA containing an A-tract. Nucleic Acids Res. 26, 5707–5718 (1998)

    Article  CAS  Google Scholar 

  18. Reményi, A. et al. Differential dimer activities of the transcription factor Oct-1 by DNA-induced interface swapping. Mol. Cell 8, 569–580 (2001)

    Article  Google Scholar 

  19. Shen, A., Higgins, D. E. & Panne, D. Recognition of AT-Rich DNA binding sites by the MogR repressor. Structure 17, 769–777 (2009)

    Article  CAS  Google Scholar 

  20. Stefl, R., Wu, H., Ravindranathan, S., Sklenar, V. & Feigon, J. DNA A-tract bending in three dimensions: solving the dA4T4 vs. dT4A4 conundrum. Proc. Natl Acad. Sci. USA 101, 1177–1182 (2004)

    Article  CAS  ADS  Google Scholar 

  21. Tolstorukov, M. Y., Colasanti, A. V., McCandlish, D. M., Olson, W. K. & Zhurkin, V. B. A novel roll-and-slide mechanism of DNA folding in chromatin: implications for nucleosome positioning. J. Mol. Biol. 371, 725–738 (2007)

    Article  CAS  Google Scholar 

  22. Watkins, S., van Pouderoyen, G. & Sixma, T. K. Structural analysis of the bipartite DNA-binding domain of Tc3 transposase bound to transposon DNA. Nucleic Acids Res. 32, 4306–4312 (2004)

    Article  CAS  Google Scholar 

  23. Aggarwal, A. K., Rodgers, D. W., Drottar, M., Ptashne, M. & Harrison, S. C. Recognition of a DNA operator by the repressor of phage 434: a view at high resolution. Science 242, 899–907 (1988)

    Article  CAS  ADS  Google Scholar 

  24. Davey, C. A., Sargent, D. F., Luger, K., Maeder, A. W. & Richmond, T. J. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J. Mol. Biol. 319, 1097–1113 (2002)

    Article  CAS  Google Scholar 

  25. Trifonov, E. N. & Sussman, J. L. The pitch of chromatin DNA is reflected in its nucleotide sequence. Proc. Natl Acad. Sci. USA 77, 3816–3820 (1980)

    Article  CAS  ADS  Google Scholar 

  26. Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006)

    Article  CAS  ADS  Google Scholar 

  27. Satchwell, S. C., Drew, H. R. & Travers, A. A. Sequence periodicities in chicken nucleosome core DNA. J. Mol. Biol. 191, 659–675 (1986)

    Article  CAS  Google Scholar 

  28. Travers, A. A. & Klug, A. in DNA Topology and its Biological Effects (eds Cozzarelli, N. R. & Wang, J. C.) 57–106 (Cold Spring Harbor Press, 1990)

    Google Scholar 

  29. Field, Y. et al. Distinct modes of regulation by chromatin encoded through nucleosome positioning signals. PLOS Comput. Biol. 4, e1000216 (2008)

    Article  Google Scholar 

  30. Segal, E. & Widom, J. Poly(dA:dT) tracts: major determinants of nucleosome organization. Curr. Opin. Struct. Biol. 19, 65–71 (2009)

    Article  CAS  Google Scholar 

  31. Honig, B. & Nicholls, A. Classical electrostatics in biology and chemistry. Science 268, 1144–1149 (1995)

    Article  CAS  ADS  Google Scholar 

  32. Jayaram, B., Sharp, K. A. & Honig, B. The electrostatic potential of B-DNA. Biopolymers 28, 975–993 (1989)

    Article  CAS  Google Scholar 

  33. Tsai, C. J., Lin, S. L., Wolfson, H. J. & Nussinov, R. Studies of protein-protein interfaces: a statistical analysis of the hydrophobic effect. Protein Sci. 6, 53–64 (1997)

    Article  CAS  Google Scholar 

  34. Nadassy, K., Wodak, S. J. & Janin, J. Structural features of protein-nucleic acid recognition sites. Biochemistry 38, 1999–2017 (1999)

    Article  CAS  Google Scholar 

  35. Luscombe, N. M., Laskowski, R. A. & Thornton, J. M. Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level. Nucleic Acids Res. 29, 2860–2874 (2001)

    Article  CAS  Google Scholar 

  36. Kissinger, C. R., Liu, B. S., Martin-Blanco, E., Kornberg, T. B. & Pabo, C. O. Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: a framework for understanding homeodomain-DNA interactions. Cell 63, 579–590 (1990)

    Article  CAS  Google Scholar 

  37. Meinke, G. & Sigler, P. B. DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B. Nature Struct. Biol. 6, 471–477 (1999)

    Article  CAS  Google Scholar 

  38. Gearhart, M. D., Holmbeck, S. M., Evans, R. M., Dyson, H. J. & Wright, P. E. Monomeric complex of human orphan estrogen related receptor-2 with DNA: a pseudo-dimer interface mediates extended half-site recognition. J. Mol. Biol. 327, 819–832 (2003)

    Article  CAS  Google Scholar 

  39. Rohs, R., West, S. M., Liu, P. & Honig, B. Nuance in the double-helix and its role in protein-DNA recognition. Curr. Opin. Struct. Biol. 19, 171–177 (2009)

    Article  CAS  Google Scholar 

  40. Richmond, T. J. & Davey, C. A. The structure of DNA in the nucleosome core. Nature 423, 145–150 (2003)

    Article  CAS  ADS  Google Scholar 

  41. Locasale, J. W., Napoli, A. A., Chen, S., Berman, H. M. & Lawson, C. L. Signatures of protein-DNA recognition in free DNA binding sites. J. Mol. Biol. 386, 1054–1065 (2009)

    Article  CAS  Google Scholar 

  42. Tolstorukov, M. Y., Virnik, K. M., Adhya, S. & Zhurkin, V. B. A-tract clusters may facilitate DNA packaging in bacterial nucleoid. Nucleic Acids Res. 33, 3907–3918 (2005)

    Article  CAS  Google Scholar 

  43. Parker, S. C., Hansen, L., Abaan, H. O., Tullius, T. D. & Margulies, E. H. Local DNA topography correlates with functional noncoding regions of the human genome. Science 324, 389–392 (2009)

    Article  CAS  ADS  Google Scholar 

  44. Lavery, R. & Sklenar, H. Defining the structure of irregular nucleic acids: conventions and principles. J. Biomol. Struct. Dyn. 6, 655–667 (1989)

    Article  CAS  Google Scholar 

  45. Rocchia, W. et al. Rapid grid-based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: applications to the molecular systems and geometric objects. J. Comput. Chem. 23, 128–137 (2002)

    Article  CAS  Google Scholar 

  46. Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia, C. SCOP: a structural classification of proteins database for the investigation of sequences and structures. J. Mol. Biol. 247, 536–540 (1995)

    CAS  PubMed  Google Scholar 

  47. Petrey, D. & Honig, B. GRASP2: visualization, surface properties, and electrostatics of macromolecular structures and sequences. Methods Enzymol. 374, 492–509 (2003)

    Article  CAS  Google Scholar 

  48. McDonald, I. K. & Thornton, J. M. Satisfying hydrogen bonding potential in proteins. J. Mol. Biol. 238, 777–793 (1994)

    Article  CAS  Google Scholar 

  49. Brenner, S. E., Koehl, P. & Levitt, M. The ASTRAL compendium for protein structure and sequence analysis. Nucleic Acids Res. 28, 254–256 (2000)

    Article  CAS  Google Scholar 

  50. Cornell, W. D. et al. A 2nd generation force-field for the simulation of proteins, nucleic-acids, and organic-molecules. J. Am. Chem. Soc. 117, 5179–5197 (1995)

    Article  CAS  Google Scholar 

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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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Author notes

  1. Alona Sosinsky

    Present address: Present address: Institute of Structural and Molecular Biology, School of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK.,

  2. Remo Rohs and Sean M. West: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics, Columbia University, 1130 Saint Nicholas Avenue, New York, New York 10032, USA,

    Remo Rohs, Sean M. West, Alona Sosinsky, Peng Liu & Barry Honig

  2. Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th Street, HHSC 1104, New York, New York 10032, USA,

    Richard S. Mann

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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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