Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 44, Pages 27132-27140Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2004563117
Keywords
cell-cell adhesion; molecular dynamics simulations; cryo-electron tomography; desmosome
Categories
Funding
- Max Planck Society
- Schroedinger Fellowship from the Fonds zur Forderung der wissenschaftlichen Forschung (FWF) [43232-B28]
- Deutsche Forschungsgemeinschaft (DFG) INST Grant [161/813-1]
- DFG [FR 1653/6-1, FR 1653/13-1, FR 1653/14-1, SFB902]
- LOEWE Schwerpunkt Dynamem
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Desmosomes are cell-cell junctions that link tissue cells experiencing intense mechanical stress. Although the structure of the desmosomal cadherins is known, the desmosome architecture-which is essential for mediating numerous functions-remains elusive. Here, we recorded cryo-electron tomograms (cryo-ET) in which individual cadherins can be discerned; they appear variable in shape, spacing, and tilt with respect to the membrane. The resulting sub-tomogram average reaches a resolution of similar to 26 angstrom, limited by the inherent flexibility of desmosomes. To address this challenge typical of dynamic biological assemblies, we combine sub-tomogram averaging with atomistic molecular dynamics (MD) simulations. We generate models of possible cadherin arrangements and perform an in silico screening according to biophysical and structural properties extracted from MD simulation trajectories. We find a truss-like arrangement of cadherins that resembles the characteristic footprint seen in the electron micrograph. The resulting model of the desmosomal architecture explains their unique biophysical properties and strength.
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