Transforming binding affinities from three dimensions to two with application to cadherin clustering (original) (raw)

Nature volume 475, pages 510–513 (2011)Cite this article

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Abstract

Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins1. For example, the association of membrane proteins with proteins on different cells (_trans_-interactions) can drive the oligomerization of proteins on the same cell2 (_cis_-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation3. A finding of general relevance is that changes in interdomain motion on _trans_-binding have a crucial role in driving the lateral, _cis_-, clustering of adhesion receptors.

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Acknowledgements

This work was supported by National Science Foundation grant MCB-0918535 (to B.H.) and National Institutes of Health grant R01 GM062270-07 (to L.S.). The financial support of the US-Israel Binational Science Foundation (grant no. 2006-401, to A.B.-S., B.H. and L.S.) and the Israel Science Foundation (ISF 1448/10 and 695/06) (to A.B.-S.) is acknowledged. We thank E. Sackmann for an email exchange concerning membrane fluctuations.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, 10032, New York, USA
    Yinghao Wu, Jeremie Vendome, Lawrence Shapiro & Barry Honig
  2. Howard Hughes Medical Institute, Columbia University, New York, 10032, New York, USA
    Yinghao Wu, Jeremie Vendome & Barry Honig
  3. Center for Computational Biology and Bioinformatics, Columbia University, New York, 10032, New York, USA
    Yinghao Wu, Jeremie Vendome & Barry Honig
  4. Edward S. Harkness Eye Institute, Columbia University, New York, 10032, New York, USA
    Lawrence Shapiro
  5. Institute of Chemistry and the Fritz Haber Research Center, The Hebrew University, Jerusalem 91904, Israel
    Avinoam Ben-Shaul

Authors

  1. Yinghao Wu
  2. Jeremie Vendome
  3. Lawrence Shapiro
  4. Avinoam Ben-Shaul
  5. Barry Honig

Contributions

Y.W., J.V., L.S., B.H. and A.B.-S. designed the research; Y.W. performed the multiscale simulations; J.V. carried out the all-atom molecular dynamics simulations; Y.W., B.H. and A.B.-S. analysed the data; Y.W., A.B.-S. and B.H. contributed analytic tools; and Y.W., L.S., B.H. and A.B.-S. wrote the paper.

Corresponding authors

Correspondence toAvinoam Ben-Shaul or Barry Honig.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Data, Supplementary Figures 1-5 with legends, Supplementary Table 1 and additional references. (PDF 451 kb)

Supplementary Movie 1

This movie shows domain fluctuations in monomer generated by coarse-grained Monte-Carlo simulations. (MOV 4233 kb)

Supplementary Movie 2

This movie shows domain fluctuations in trans-dimer generated by coarse-grained Monte-Carlo simulations. (MOV 10229 kb)

Supplementary Movie 3

This movie shows lattice simulation of junction formation. (MOV 5828 kb)

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Wu, Y., Vendome, J., Shapiro, L. et al. Transforming binding affinities from three dimensions to two with application to cadherin clustering.Nature 475, 510–513 (2011). https://doi.org/10.1038/nature10183

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Editorial Summary

Interactions on the cell surface

Relating the strengths of interactions occurring in two dimensions on membrane surfaces to those measured in three dimensions in solution is a perennial problem in cell biology. Barry Honig and colleagues use a computational and theoretical approach that enables a new type of structurally- and biophysically-driven analysis of processes that occur on cell surfaces. Applying this approach to cadherin-mediated cell adhesion reveals novel principles about how cell–cell interactions drive receptor clustering on membrane surfaces.