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Cryo- Electron Microscopy of vitreous sections of biological cells and tissues

Final Activity Report Summary - TOVIS (Cryo- electron microscopy of vitreous sections of biological cells and tissues)

Cell-cell adhesion is important in binding the cells of normal tissue together thus maintaining tissue integrity. They also play key roles in embryonic development, skin and heart diseases, and cancer. The adhesions concerned, called desmosomes are small regions on cell surfaces where adhesion molecules, called cadherins, are concentrated and connected to the cell cytoskeleton through a set of proteins making up an electron-dense region called desmosomal plaque.

Our objective was to resolve the molecular structure of the desmosome. Despite considerable efforts, the molecular organisation of desmosome has been obscure. The desmosome is a large macromolecular complex which makes it inaccessible to conventional structural determination and biochemical methods. Using cryo-electron tomography of vitreous sections from human epidermis we were able to visualise the three-dimensional (3D) molecular architecture of desmosomal cadherins at close to native conditions. The resulting 3D reconstructions showed a regular array of densities at app.70 Angstrom intervals along the midline with a curved shape resembling the X-ray structure of C-cadherin. 3D image processing of extracted sub-tomograms revealed the cadherin organisation. After fitting the C-cadherin atomic structure into the averaged sub-tomograms, we saw a periodic arrangement of a trans W-like and a cis V-like interaction corresponding to molecules from opposing and the same cell membrane, respectively.

These results provide the first molecular model of cadherin organisation in vivo that is compatible with previous EM data and X-ray crystal structures of isolated cadherins. Furthermore, the resulting model of cadherin organisation explains existing two-dimensional data and yields insights into a possible mechanism of cadherin-based cell adhesion.