Desmosome architecture derived from molecular dynamics simulations and cryo-electron tomography

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 44; pp. 27132 - 27140
• Main Authors: Sikora, Mateusz, Ermel, Utz H., Seybold, Anna, Kunz, Michael, Calloni, Giulia, Reitzc, Julian, Vabulas, R. Martin, Hummer, Gerhard, Frangakis, Achilleas S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.11.2020
• Subjects: Cadherins; Cadherins - chemistry; Cadherins - metabolism; Cell junctions; Desmosomes; Desmosomes - chemistry; Desmosomes - metabolism; Desmosomes - physiology; Electron micrographs; Electron Microscope Tomography - methods; Electrons; Humans; Intercellular Junctions; Molecular dynamics; Molecular Dynamics Simulation; Physical Sciences; Simulation; molecular dynamics simulations; desmosome; cell–cell adhesion; cryo-electron tomography
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2004563117

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 subtomogram average reaches a resolution of ∼26 Å, 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.