Abstract
Desmosomes are cadherin-based adhesive intercellular junctions, which are present in tissues such as heart and skin. Despite considerable efforts, the molecular interfaces that mediate adhesion remain obscure. Here we apply cryo-electron tomography of vitreous sections from human epidermis to visualize the three-dimensional molecular architecture of desmosomal cadherins at close-to-native conditions. The three-dimensional reconstructions show a regular array of densities at ∼70 Å intervals along the midline, with a curved shape resembling the X-ray structure of C-cadherin, a representative ‘classical’ cadherin. Model-independent three-dimensional image processing of extracted sub-tomograms reveals the cadherin organization. After fitting the C-cadherin atomic structure into the averaged sub-tomograms, we see a periodic arrangement of a trans W-like and a cis V-like interaction corresponding to molecules from opposing membranes and the same cell membrane, respectively. The resulting model of cadherin organization explains existing two-dimensional data and yields insights into a possible mechanism of cadherin-based cell adhesion.
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EMBL/GenBank/DDBJ
Data deposits
The cadherin map has been deposited in the EBI Macromolecular Structure Database with accession number EMD-1374. The software is available at http://www-db.embl.de/jss/EmblGroupsHD/g_247?sP=7 or on request.
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Acknowledgements
We thank H. Saibil, B. Boettcher, A. Seybert and J. Dubochet for suggestions and for critically reading the manuscript. This work was supported by grants from the FP6 Marie Curie mobility network and EMBO fellowships to A.A.-A. and from the FP6 3DEM network of excellence to A.S.F.
Author Contributions A.A.-A. prepared the samples, and recorded and interpreted the data sets. D.C.D. developed algorithms for aligning and classifying the data. M.J.B. performed a structural bioinformatics analysis. A.S.F. analysed the data. A.A.-A. and A.S.F. wrote the manuscript.
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Supplementary Information
This file contains Supplementary Tables 1-2, Supplementary Figures S1-S5 with Legends and Legends to Supplementary Movies 1-2. (PDF 1878 kb)
Supplementary Movie 1
This file contains Supplementary Movie 1 which shows visualization of slices presented in Fig. 1b and the isosurface images in Fig. 1c. (MOV 24389 kb)
Supplementary Movie 2
This file contains Supplementary Movie 2 which shows visualization of the fitting of the cadherin molecules onto the density of the averaged sub-tomograms. The arrangement of the cadherin molecules with respect to each other is also visible, as are the alternating cis-trans interactions. (MOV 4758 kb)
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Al-Amoudi, A., Díez, D., Betts, M. et al. The molecular architecture of cadherins in native epidermal desmosomes. Nature 450, 832–837 (2007). https://doi.org/10.1038/nature05994
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DOI: https://doi.org/10.1038/nature05994
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