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Sequence-specific dynamics modulate recognition specificity in WW domains

Nature Structural & Molecular Biology volume 14, pages 325–331 (2007)Cite this article

Abstract

The current canon attributes the binding specificity of protein-recognition motifs to distinctive chemical moieties in their constituent amino acid sequences. However, we show for a WW domain that the sequence crucial for specificity is an intrinsically flexible loop that partially rigidifies upon ligand docking. A single-residue deletion in this loop simultaneously reduces loop flexibility and ligand binding affinity. These results suggest that sequences of recognition motifs may reflect natural selection of not only chemical properties but also dynamic modes that augment specificity.

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Figure 1: PIN1-WW (1I6C) colored according to dynamics.
Figure 2: Reduced spectral density values Jeff(0) and 〈J(ωH)〉 of backbone NH bonds for apo–PIN1-WW (residues 6–39) at 278 K and 16.4 T.
Figure 3: Temperature dependence of apo–PIN1-WW backbone proton 1HN resonances of Arg17, Ser18, Ser19 and Gly20 in recognition loop I.
Figure 4: 15N R1ρ relaxation dispersion for Arg17 backbone NH.
Figure 5: Order parameters S2 of backbone NH bonds for apo– and Cdc25-complexed PIN1-WW at 278 K, 16.4 T.
Figure 6
Figure 7: 1H-15N steady-state NOE for wild-type PIN1-WW compared with the deletion mutant WWS19 at 16.4 T or 18.8 T, and 278 K.
Figure 8: Temperature dependence of the backbone NH resonance of Arg17.
Figure 9: Loop I energy-minimized conformations.

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Acknowledgements

We thank H. Goodson, P. Clark, G. Pasat and B. Wilson for critical reading of the manuscript. This work was supported in part by the American Chemical Society Petroleum Research Fund PRF no. 44640-G4.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, 46556, Indiana, USA

    Tao Peng, John S Zintsmaster, Andrew T Namanja & Jeffrey W Peng

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Correspondence to Jeffrey W Peng.

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Supplementary information

Supplementary Fig. 1

NMR titration. (PDF 156 kb)

Supplementary Table 1

Dynamic parameters. (PDF 87 kb)

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Peng, T., Zintsmaster, J., Namanja, A. et al. Sequence-specific dynamics modulate recognition specificity in WW domains. Nat Struct Mol Biol 14, 325–331 (2007). https://doi.org/10.1038/nsmb1207

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