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Transition states for protein folding have native topologies despite high structural variability

Nature Structural & Molecular Biology volume 11, pages 443–449 (2004)Cite this article

Abstract

We present a structural analysis of the folding transition states of three SH3 domains. Our results reveal that the secondary structure is not yet fully formed at this stage of folding and that the solvent is only partially excluded from the interior of the protein. Comparison of the members of the transition state ensemble with a database of native folds shows that, despite substantial local variability, the transition state structures can all be classified as having the topology characteristic of an SH3 domain. Our results suggest a mechanism for folding in which the formation of a network of interactions among a subset of hydrophobic residues ensures that the native topology is generated. Such a mechanism enables high fidelity in folding while minimizing the need to establish a large number of specific interactions in the conformational search.

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Figure 1: Structure and sequence of the SH3 domains used in this study.
Figure 2: Three representations of the TSE of src SH3.
Figure 3: Transition state ensembles.
Figure 4: Structural classification of transition state structures using a distance matrix alignment to the SCOP domain database22.
Figure 5: Solvent accessibility and secondary structure in the TSE of src SH3.
Figure 6: Interaction network in the native and transition states.
Figure 7: Key network of interactions in the transition state for folding.

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Acknowledgements

We are very grateful to M. Karplus for continuing interest and support. We thank J. Clarke, X. Salvatella, L. Serrano and J. Winther for valuable discussions, and A. Davidson and L. Serrano for sharing experimental data before publication. We are grateful to L. Serrano for providing FOLD-X, B. Rost for DSSPcont and L. Holm for DaliLite. K.L.L. is supported by the Danish Research Agency. M.V. is a Royal Society University Research Fellow. The research of C.M.D. is supported in part by a Programme Grant from the Wellcome Trust and by the Leverhulme Trust.

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  1. University of Cambridge, University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK

    Kresten Lindorff-Larsen, Michele Vendruscolo & Christopher M Dobson

  2. Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, Zürich, 8057, Switzerland

    Emanuele Paci

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Correspondence to Christopher M Dobson.

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Lindorff-Larsen, K., Vendruscolo, M., Paci, E. et al. Transition states for protein folding have native topologies despite high structural variability. Nat Struct Mol Biol 11, 443–449 (2004). https://doi.org/10.1038/nsmb765

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