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Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins

Nature Structural & Molecular Biology volume 18, pages 693700 (2011) | Download Citation

Abstract

Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal β-strands. We use molecular simulations, measurements of binding affinities and X-ray crystallography to provide a detailed picture of the structural and energetic factors that control the adhesive dimerization of cadherins. We show that strand swapping in EC1 is driven by conformational strain in cadherin monomers that arises from the anchoring of their short N-terminal strand at one end by the conserved Trp2 and at the other by ligation to Ca2+ ions. We also demonstrate that a conserved proline-proline motif functions to avoid the formation of an overly tight interface where affinity differences between different cadherins, crucial at the cellular level, are lost. We use these findings to design site-directed mutations that transform a monomeric EC2-EC3 domain cadherin construct into a strand-swapped dimer.

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Acknowledgements

This work was supported by US National Science Foundation Grant MCB-0918535 (to B.H.) and National Institutes of Health Grant R01 GM062270–07 (to L.S.).

Author information

Author notes

    • Shoshana Posy

    Present address: Computer-Assisted Drug Design, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.

    • Jeremie Vendome
    •  & Shoshana Posy

    These authors contributed equally to this work.

Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.

    • Jeremie Vendome
    • , Shoshana Posy
    • , Xiangshu Jin
    • , Fabiana Bahna
    • , Goran Ahlsen
    • , Lawrence Shapiro
    •  & Barry Honig
  2. Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.

    • Jeremie Vendome
    • , Shoshana Posy
    • , Goran Ahlsen
    •  & Barry Honig
  3. Howard Hughes Medical Institute, Columbia University, New York, New York, USA.

    • Jeremie Vendome
    • , Shoshana Posy
    • , Xiangshu Jin
    • , Fabiana Bahna
    •  & Barry Honig
  4. Edward S. Harkness Eye Institute, Columbia University, New York, New York, USA.

    • Lawrence Shapiro

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Contributions

J.V. performed and analyzed the simulations; J.V. and S.P. designed the mutants; F.B. produced all the wild-type and mutant proteins; G.A. performed and analyzed the AUC experiments; X.J. determined and refined the crystal structures; J.V., L.S. and B.H. designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lawrence Shapiro or Barry Honig.

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https://doi.org/10.1038/nsmb.2051

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