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Membrane fluctuations mediate lateral interaction between cadherin bonds

Abstract

The integrity of living tissues is maintained by adhesion domains of trans-bonds formed between cadherin proteins residing on opposing membranes of neighbouring cells. These domains are stabilized by lateral cis-interactions between the cadherins on the same cell. However, the origin of cis-interactions remains perplexing since they are detected only in the context of trans-bonds. By combining experimental, analytical and computational approaches, we identify bending fluctuations of membranes as a source of long-range cis-interactions, and a regulator of trans-interactions. Specifically, nanometric membrane bending and fluctuations introduce cooperative effects that modulate the affinity and binding/unbinding rates for trans-dimerization, dramatically affecting the nucleation and growth of adhesion domains. Importantly, this regulation relies on physical principles and not on details of protein–protein interactions. These omnipresent fluctuations can thus act as a generic control mechanism in all types of cell adhesion, suggesting a hitherto unknown physiological role for recently identified active fluctuations of cellular membranes.

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Figure 1: The model system for cell–cell adhesion.
Figure 2: The morphology of adhesion domains in the steady state depends on parameters describing the unbound state, namely the mean separation h0 between the vesicle membrane and the substrate, and the fluctuation amplitude of the vesicle membrane ξ0.
Figure 3: Modelling the coupling between shape and fluctuations of the membrane and cadherin cluster formation.
Figure 4: Effective rates (in units of the intrinsic reaction rate k0) and affinity (in units of kBT) for trans-dimerization and cis-cluster formation.
Figure 5: Comparison of growth dynamics of cadherin adhesions in experiments and matching Monte Carlo simulations.
Figure 6: Comparison of experiments and simulations.

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Acknowledgements

A.-S.S. and T.B. were funded from the grant ERC StG 2013-337283 and K.S. from ERC-StG 307104FP of the European Research Council. A.-S.S. and D.S. were supported by the Research Training Group 1962 at the Friedrich-Alexander-Universität Erlangen-Nürnberg. This work has partly been supported by AMIDEX (no. ANR-11-IDEX-0001-02), the Croatian Science Foundation (IP-11-2013-8238 CompSoLS-MolFlex) and the BigThera project at FAU.

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The project was conceived and supervised by A.-S.S., K.S., U.S. and R.M. The experimental set-up was established by S.F.F. and K.S. and applied to the current problem by S.F.F. Data analysis was performed by S.F.F., D.S., K.S. and A.-S.S. The simulation set-up was built by T.B. and A.-S.S., and executed by T.B. The theoretical model was developed by D.S. and A.-S.S. with the help of T.B. and U.S. All authors contributed to the interpretation of results. The article was written by T.B., D.S., S.F.F., K.S. and A.-S.S.

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Correspondence to Ana-Sunčana Smith.

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Fenz, S., Bihr, T., Schmidt, D. et al. Membrane fluctuations mediate lateral interaction between cadherin bonds. Nature Phys 13, 906–913 (2017). https://doi.org/10.1038/nphys4138

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