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The molecular architecture of cadherins in native epidermal desmosomes

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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Figure 1: Visualization of the desmosomal region.
Figure 2: Tomographic slices of the desmosome.
Figure 3: Visualization of the average of the sub-tomograms.
Figure 4: Stereo view of the C-cadherin X-ray structures 14 fitted to the average of the sub-tomograms (see also Supplementary Movie 2).
Figure 5: Comparison of the fitted cadherins with the manually adjusted model of the interfaces of N-cadherin15.
Figure 6: Comparison of the modelled desmosome with 2D transmission CEMOVIS data of the skin.

Accession codes

Primary accessions

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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Correspondence to Achilleas S. Frangakis.

Supplementary information

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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