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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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 A∗MIDEX (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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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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DOI: https://doi.org/10.1038/nphys4138
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