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 ∼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.

桥粒是连接经历强烈机械应力的组织细胞的细胞-细胞连接。尽管桥粒钙粘蛋白的结构是已知的，但桥粒结构——对于调节多种功能至关重要——仍然难以捉摸。在这里，我们记录了冷冻电子断层扫描 (cryo-ET)，其中可以辨别单个钙粘蛋白。它们在形状、间距和相对于膜的倾斜方面看起来是可变的。由此产生的亚断层照片平均值达到~26Å的分辨率，受到桥粒固有灵活性的限制。为了应对动态生物组装的典型挑战，我们将亚断层平均与原子分子动力学 (MD) 模拟相结合。我们生成可能的钙粘蛋白排列模型，并根据从 MD 模拟轨迹中提取的生物物理和结构特性进行计算机筛选。我们发现钙粘蛋白的桁架状排列类似于电子显微照片中看到的特征足迹。由此产生的桥粒结构模型解释了它们独特的生物物理特性和强度。