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Observation of signal transduction in three-dimensional domain swapping

Nature Structural Biology volume 8, pages 888–892 (2001)Cite this article

Abstract

p13suc1 (suc1) has two native states, a monomer and a domain-swapped dimer. The structure of each subunit in the dimer is identical to that of the monomer, except for the hinge loop that connects the exchanging domains. Here we find that single point mutations at sites throughout the protein and ligand binding both shift the position of the equilibrium between monomer and dimer. The hinge loop was shown previously to act as a loaded molecular spring that releases tension present in the monomer by adopting an alternative conformation in the dimer. The results here indicate that the release of strain propagates throughout the entire protein and alters the energetics of regions remote from the hinge. Our data illustrate how the signal conferred by the conformational change of a protein loop, elicited by domain swapping, ligand binding or mutation, can be sensed by a distant active site. This work highlights the potential role of strained loops in proteins: the energy they store can be used for both signal transduction and allostery, and they could steer the evolution of protein function. Finally, a structural mechanism for the role of suc1 as an adapter molecule is proposed.

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Figure 1: Schematic representation of the suc1 structures.
Figure 2: Measurement of the monomer-dimer equilibrium of suc1.
Figure 3: Mapping the difference in the effect of mutations on the monomer-dimer equilibrium onto a schematic representation of the monomer structure of suc1.
Figure 4: Ligand binding experiments of suc1.

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Acknowledgements

This work was supported by the MRC of the UK. L.S.I. was supported by a Career Development Award from the MRC of the UK. J.W.H.S. and F.R. were supported by Marie Curie Training and Mobility of Research Fellowships from the E.C. A.F. is supported by a Human Frontier Science Program long term fellowship. We thank A.R. Fersht and J. Clarke for useful discussions and S. Kazmirski for help with analyzing the crystal structures.

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Authors and Affiliations

  1. Centre for Protein Engineering, University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW

    Joost W.H. Schymkowitz, Frederic Rousseau, Hannah R. Wilkinson, Assaf Friedler & Laura S. Itzhaki

  2. MRC Centre, Hills Road, Cambridge, CB2 2QH, UK

    Joost W.H. Schymkowitz, Frederic Rousseau, Hannah R. Wilkinson, Assaf Friedler & Laura S. Itzhaki

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  1. Joost W.H. Schymkowitz
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Correspondence to Laura S. Itzhaki.

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Schymkowitz, J., Rousseau, F., Wilkinson, H. et al. Observation of signal transduction in three-dimensional domain swapping. Nat Struct Mol Biol 8, 888–892 (2001). https://doi.org/10.1038/nsb1001-888

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