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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aplin, A. E., Howe, A. K. & Juliano, R. L. Cell adhesion molecules, signal transduction and cell growth. Curr. Opin. Cell Biol. 11, 737–744 (1999)
Aricescu, A. R. & Jones, E. Y. Immunoglobulin superfamily cell adhesion molecules: zippers and signals. Curr. Opin. Cell Biol. 19, 543–550 (2007)
Wu, Y. et al. Cooperativity between trans and cis interactions in cadherin-mediated junction formation. Proc. Natl Acad. Sci. USA 107, 17592–17597 (2010)
Dustin, M. L., Ferguson, L. M., Chan, P. Y., Springer, T. A. & Golan, D. E. Visualization of CD2 interaction with LFA-3 and determination of the two-dimensional dissociation constant for adhesion receptors in a contact area. J. Cell Biol. 132, 465–474 (1996)
Dustin, M. L., Bromley, S. K., Davis, M. M. & Zhu, C. Identification of self through two-dimensional chemistry and synapses. Annu. Rev. Cell Dev. Biol. 17, 133–157 (2001)
Bell, G. I. Models for the specific adhesion of cells to cells. Science 200, 618–627 (1978)
Bell, G. I., Dembo, M. & Bongrand, P. Cell adhesion. Competition between nonspecific repulsion and specific bonding. Biophys. J. 45, 1051–1064 (1984)
Chen, C. P., Posy, S., Ben-Shaul, A., Shapiro, L. & Honig, B. H. Specificity of cell-cell adhesion by classical cadherins: critical role for low-affinity dimerization through beta-strand swapping. Proc. Natl Acad. Sci. USA 102, 8531–8536 (2005)
Patel, S. D. et al. Type II cadherin ectodomain structures: implications for classical cadherin specificity. Cell 124, 1255–1268 (2006)
Harrison, O. J. et al. The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins. Structure 19, 244–256 (2011)
Katsamba, P. et al. Linking molecular affinity and cellular specificity in cadherin-mediated adhesion. Proc. Natl Acad. Sci. USA 106, 11594–11599 (2009)
Gov, N. S. & Safran, S. A. Red blood cell membrane fluctuations and shape controlled by ATP-induced cytoskeletal defects. Biophys. J. 88, 1859–1874 (2005)
Zilker, A., Engelhardt, H. & Sackmann, E. Dynamic reflection interference contrast (RIC-) microscopy: a new method to study surface excitations of cells and to measure membrane bending elastic moduli. J. Phys. 48, 2139–2151 (1987)
Hill, T. L. An Introduction to Statistical Thermodynamics 147–176 (Dover, 1987)
Boggon, T. J. et al. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296, 1308–1313 (2002)
Dustin, M. L. et al. Low affinity interaction of human or rat T cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity. J. Biol. Chem. 272, 30889–30898 (1997)
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)
Huppa, J. B. et al. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463, 963–967 (2010)
Milstein, O. et al. Nanoscale increases in CD2–CD48-mediated intermembrane spacing decrease adhesion and reorganize the immunological synapse. J. Biol. Chem. 283, 34414–34422 (2008)
Atilgan, A. R. et al. Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys. J. 80, 505–515 (2001)
Li, G. H. & Cui, Q. A coarse-grained normal mode approach for macromolecules: an efficient implementation and application to Ca2+-ATPase. Biophys. J. 83, 2457–2474 (2002)
Tama, F., Gadea, F. X., Marques, O. & Sanejouand, Y. H. Building-block approach for determining low-frequency normal modes of macromolecules. Proteins 41, 1–7 (2000)
Van Der Spoel, D. et al. GROMACS: fast, flexible, and free. J. Comput. Chem. 26, 1701–1718 (2005)
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.
Author information
Authors and Affiliations
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
Ethics declarations
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature10183
This article is cited by
-
Transient interactions drive the lateral clustering of cadherin-23 on membrane
Communications Biology (2023)
-
How does the same ligand activate signaling of different receptors in TNFR superfamily: a computational study
Journal of Cell Communication and Signaling (2023)
-
Dynamics and functions of E-cadherin complexes in epithelial cell and tissue morphogenesis
Marine Life Science & Technology (2023)
-
Structural insights into the contactin 1 – neurofascin 155 adhesion complex
Nature Communications (2022)
-
Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations
Communications Biology (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.