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Complete change of the protein folding transition state upon circular permutation

Nature Structural Biology volume 9, pages 818–822 (2002)Cite this article

Abstract

Reversing the loop lengths of the small protein S6 by circular permutation has a dramatic effect on the transition state structure: it changes from globally diffuse to locally condensed. The phenomenon arises from a biased dispersion of the contact energies. Stability data derived from point mutations throughout the S6 structure show that interactions between residues that are far apart in sequence are stronger than those that are close. This entropy compensation drives all parts of the protein to fold simultaneously and produces the diffuse transition-state structure typical for two-state proteins. In the circular permutant, where strong contacts and short sequence separations are engineered to concur, the transition state becomes atypically condensed and polarized. Taken together with earlier findings that S6 may also fold by a 'collapsed' trajectory with an intermediate, the results suggest that this protein may fold by a multiplicity of mechanisms. The observations indicate that the diffuse transition state of S6 is not required for folding but could be an evolutionary development to optimize cooperativity.

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Figure 1: The diffuse versus polarized distribution of φ-values in the transition state of S6wt (PDB entry 1RIS) and the circular permutant P13–14.
Figure 2: The distribution of strong side chain interactions in the S6 structure.
Figure 3: Plots of ΔΔGD-N, T ΔSFlory, d and Lmean for other two-state proteins.
Figure 4: Schematic illustration of the folding free-energy profiles for a globally diffuse nucleus and a locally condensed nucleus.

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Acknowledgements

We thank S. Plotkin, P. Wolynes and D. Thirumalai for stimulating discussions and Katarina Wallgren for technical assistance. The work was supported by the Swedish Research Council.

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Authors and Affiliations

  1. Department of Biochemistry, Umeå University, Umeå, S-901 87, Sweden

    Magnus Lindberg, Jeanette Tångrot & Mikael Oliveberg

  2. UCMP/Department of Computing Science, Umeå University, Umeå, S-901 87, Sweden

    Jeanette Tångrot

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Correspondence to Mikael Oliveberg.

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Lindberg, M., Tångrot, J. & Oliveberg, M. Complete change of the protein folding transition state upon circular permutation. Nat Struct Mol Biol 9, 818–822 (2002). https://doi.org/10.1038/nsb847

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