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Membrane fluctuations mediate lateral interaction between cadherin bonds


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.


  1. 1

    Leckband, D. & Sivasankar, S. Cadherin recognition and adhesion. Curr. Opin. Cell Biol. 24, 620–627 (2012).

    Google Scholar 

  2. 2

    Lecuit, T. & Yap, A. S. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat. Cell Biol. 17, 533–539 (2015).

    Google Scholar 

  3. 3

    Wu, Y., Vendome, J., Shapiro, L., Ben-Shaul, A. & Honig, B. Transforming binding affinities from three dimensions to two with application to cadherin clustering. Nature 475, 510–513 (2011).

    Google Scholar 

  4. 4

    Volk, T., Cohen, O. & Geiger, B. Formation of heterotypic adherens-type junctions between L-CAM-containing liver cells and A-CAM-containing lens cells. Cell 50, 987–994 (1987).

    Google Scholar 

  5. 5

    Ayalon, O. et al. Spatial and temporal relationships between cadherins and pecam-1 in cell–cell junctions of human endothelial cells. J. Cell Biol. 126, 247–258 (1994).

    Google Scholar 

  6. 6

    Strale, P.-O. et al. The formation of ordered nanoclusters controls cadherin anchoring to actin and cell–cell contact fluidity. J. Cell Biol. 210, 333–346 (2015).

    Google Scholar 

  7. 7

    Engl, W. et al. Actin dynamics modulate mechanosensitive immobilization of E-cadherin at adherens junctions. Nat. Cell Biol. 16, 584–591 (2014).

    Google Scholar 

  8. 8

    Bello, S. M. et al. Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons. J. Neurosci. 32, 490–505 (2012).

    Google Scholar 

  9. 9

    Katsamba, P. et al. Linking molecular affinity and cellular specificity in cadherin-mediated adhesion. Proc. Natl Acad. Sci. USA 106, 11594–11599 (2009).

    ADS  Google Scholar 

  10. 10

    Gumbiner, B. M. Regulation of cadherin-mediated adhesion in morphogenesis. Nat. Rev. Mol. Cell Biol. 6, 622–634 (2005).

    Google Scholar 

  11. 11

    Jeanes, A., Gottardi, C. J. & Yap, A. S. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27, 6920–6929 (2008).

    Google Scholar 

  12. 12

    Biswas, K. H. et al. E-cadherin junction formation involves an active kinetic nucleation process. Proc. Natl Acad. Sci. USA 112, 10932–10937 (2015).

    ADS  Google Scholar 

  13. 13

    Rakshit, S. & Sivasankar, S. Biomechanics of cell adhesion: how force regulates the lifetime of adhesive bonds at the single molecule level. Phys. Chem. Chem. Phys. 16, 2211–2223 (2014).

    Google Scholar 

  14. 14

    Sivasankar, S. et al. Characterizing the initial encounter complex in cadherin adhesion. Structure 17, 1075–1081 (2009).

    Google Scholar 

  15. 15

    Harrison, O. J. et al. Two-step adhesive binding by classical cadherins. Nat. Struct. Mol. Biol. 17, 348–357 (2010).

    Google Scholar 

  16. 16

    Boggon, T. J. et al. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296, 1308–1313 (2002).

    ADS  Google Scholar 

  17. 17

    Fenz, S. F. & Sengupta, K. Giant vesicles as cell models. Integr. Biol. 4, 982–995 (2012).

    Google Scholar 

  18. 18

    Vendome, J. et al. Structural and energetic determinants of adhesive binding specificity in type I cadherins. Proc. Natl Acad. Sci. USA 111, E4175–E4184 (2014).

    Google Scholar 

  19. 19

    Harrison, O. J. et al. The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins. Structure 19, 244–256 (2011).

    Google Scholar 

  20. 20

    Taveau, J.-C. et al. Structure of artificial and natural VE-cadherin-based adherens junctions. Biochem. Soc. Trans. 36, 189–193 (2008).

    Google Scholar 

  21. 21

    Hong, S., Troyanovsky, R. B. & Troyanovsky, S. M. Spontaneous assembly and active disassembly balance adherens junction homeostasis. Proc. Natl Acad. Sci. USA 107, 3528–3533 (2010).

    ADS  Google Scholar 

  22. 22

    Ozaki, C. et al. The extracellular domains of E- and N-cadherin determine the scattered punctate localization in epithelial cells and the cytoplasmic domains modulate the localization. J. Biochem. 147, 415–425 (2010).

    Google Scholar 

  23. 23

    Hong, S., Troyanovsky, R. B. & Troyanovsky, S. M. Binding to F-actin guides cadherin cluster assembly, stability, and movement. J. Cell Biol. 201, 131–143 (2013).

    Google Scholar 

  24. 24

    Wu, Y. et al. Cooperativity between trans and cis interactions in cadherin-mediated junction formation. Proc. Natl Acad. Sci. USA 107, 17592–17597 (2010).

    ADS  Google Scholar 

  25. 25

    Brasch, J. et al. Thinking outside the cell: how cadherins drive adhesion. Trends Cell Biol. 22, 299–310 (2012).

    Google Scholar 

  26. 26

    Fenz, S. F., Merkel, R. & Sengupta, K. Diffusion and intermembrane distance: case study of avidin and E-cadherin mediated adhesion. Langmuir 25, 1074–1085 (2009).

    Google Scholar 

  27. 27

    Limozin, L. & Sengupta, K. Quantitative reflection interference contrast microscopy (RICM) in soft matter and cell adhesion. ChemPhysChem 10, 2752–2768 (2009).

    Google Scholar 

  28. 28

    Fenz, S. F. et al. Inter-membrane adhesion mediated by mobile linkers: effect of receptor shortage. Soft Matter 7, 952–962 (2011).

    ADS  Google Scholar 

  29. 29

    Sengupta, K. & Limozin, L. Adhesion of soft membranes controlled by tension and interfacial polymers. Phys. Rev. Lett. 104, 088101 (2010).

    ADS  Google Scholar 

  30. 30

    Schmidt, D. et al. Signature of a nonharmonic potential as revealed from a consistent shape and fluctuation analysis of an adherent membrane. Phys. Rev. X 4, 021023 (2014).

    Google Scholar 

  31. 31

    Rädler, J. O. et al. Fluctuation analysis of tension-controlled undulation forces between giant vesicles and solid substrates. Phys. Rev. E 51, 4526–4536 (1995).

    ADS  Google Scholar 

  32. 32

    Seifert, U. Configuration of fluid membranes and vesicles. Adv. Phys. 46, 13–137 (1997).

    ADS  Google Scholar 

  33. 33

    Schmidt, D. et al. Coexistence of dilute and densely packed domains of ligand-receptor bonds in membrane adhesion. Europhys. Lett. 99, 38003 (2012).

    ADS  Google Scholar 

  34. 34

    Bazellières, E. et al. Control of cell–cell forces and collective cell dynamics by the intercellular adhesome. Nat. Cell Biol. 17, 409–420 (2015).

    Google Scholar 

  35. 35

    Bell, G. I. Models for the specific adhesion of cells to cells. Science 200, 618–627 (1978).

    ADS  Google Scholar 

  36. 36

    Dembo, M. et al. The reaction-limited kinetics of membrane-to-surface adhesion and detachment. Proc. R. Soc. Lond. B 234, 55–83 (1988).

    ADS  Google Scholar 

  37. 37

    Bihr, T., Seifert, U. & Smith, A.-S. Multiscale approaches to protein-mediated interactions between membranes—relating microscopic and macroscopic dynamics in radially growing adhesions. New J. Phys. 17, 083016 (2015).

    ADS  Google Scholar 

  38. 38

    Monzel, C. et al. Measuring fast stochastic displacements of bio-membranes with dynamic optical displacement spectroscopy. Nat. Commun. 6, 1221–1229 (2015).

    Google Scholar 

  39. 39

    Turlier, H. et al. Equilibrium physics breakdown reveals the active nature of red blood cell flickering. Nat. Phys. 12, 513–516 (2016).

    Google Scholar 

  40. 40

    Bihr, T., Seifert, U. & Smith, A.-S. Nucleation of ligand-receptor domains in membrane adhesion. Phys. Rev. Lett. 109, 258101 (2012).

    ADS  Google Scholar 

  41. 41

    Fenz, S. F. et al. Switching from ultraweak to strong adhesion. Adv. Mater. 23, 2622–2626 (2011).

    Google Scholar 

  42. 42

    Adams, C. L. et al. Mechanisms of epithelial cell–cell adhesion and cell compaction revealed by high-resolution tracking of E-cadherin-green fluorescent protein. J. Cell Biol. 142, 1105–1119 (1998).

    Google Scholar 

  43. 43

    Perez, T.-D. et al. Immediate-early signaling induced by E-cadherin engagement and adhesion. J. Biol. Chem. 283, 5014–5022 (2008).

    Google Scholar 

  44. 44

    Smith, A.-S. et al. Force-induced growth of adhesion domains is controlled by receptor mobility. Proc. Natl Acad. Sci. USA 105, 6906–6911 (2008).

    ADS  Google Scholar 

  45. 45

    Schmidt, D. et al. Crowding of receptors induces ring-like adhesions in model membranes. Biochim. Biophys. Acta 1853, 2984–2991 (2015).

    Google Scholar 

  46. 46

    Dustin, M. L. et al. Identification of self through two-dimensional chemistry and synapses. Annu. Rev. Cell Dev. Biol. 17, 133–157 (2001).

    Google Scholar 

  47. 47

    Zhu, D.-M. et al. Analysis of two-dimensional dissociation constant of laterally mobile cell adhesion molecules. Biophys. J. 92, 1022–1034 (2007).

    ADS  Google Scholar 

  48. 48

    Hu, J., Lipowsky, R. & Weikl, T. R. Binding constants of membrane-anchored receptors and ligands depend strongly on the nanoscale roughness of membranes. Proc. Natl Acad. Sci. USA 110, 15283–15288 (2013).

    ADS  Google Scholar 

  49. 49

    Boulbitch, A., Guttenberg, Z. & Sackmann, E. Kinetics of membrane adhesion mediated by ligand-receptor interaction studied with a biomimetic system. Biophys. J. 81, 2743–2751 (2001).

    Google Scholar 

  50. 50

    Lorz, B. G. et al. Adhesion of giant vesicles mediated by weak binding of sialyl-lewisX to E-selectin in the presence of repelling poly(ethylene glycol) molecules. Langmuir 23, 12293–12300 (2007).

    Google Scholar 

  51. 51

    Wu, Y., Honig, B. & Ben-Shaul, A. Theory and simulations of adhesion receptor dimerization on membrane surfaces. Biophys. J. 104, 1221–1229 (2013).

    ADS  Google Scholar 

  52. 52

    Zidovska, A. & Sackmann, E. Brownian motion of nucleated cell envelopes impedes adhesion. Phys. Rev. Lett. 96, 048103 (2006).

    ADS  Google Scholar 

  53. 53

    Pierres, A. et al. How cells tiptoe on adhesive surfaces before sticking. Biophys. J. 94, 4114–4122 (2008).

    ADS  Google Scholar 

  54. 54

    Monzel, C. et al. Probing biomembrane dynamics by dual-wavelength reflection interference contrast microscopy. ChemPhysChem 10, 2828–2838 (2009).

    Google Scholar 

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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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The authors declare no competing financial interests.

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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).

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