Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio; The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio; Biophysics Graduate Program, The Ohio State University, Columbus, Ohio.
Biophys J. 2022 Mar 15;121(6):991-1012. doi: 10.1016/j.bpj.2022.02.008. Epub 2022 Feb 10.
Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions are responsible for directing neuronal circuits assembly. Structural models for adherens junctions formed by epithelial cadherin (CDH1) proteins indicate that their long, curved ectodomains arrange to form a periodic, two-dimensional lattice stabilized by tip-to-tip trans interactions (across junction) and lateral cis contacts. Less is known about the exact architecture of desmosomes, but desmoglein (DSG) and desmocollin (DSC) cadherin proteins are also thought to form ordered junctions. In contrast, clustered protocadherin (PCDH)-based cell-cell contacts in neuronal tissues are thought to be responsible for self-recognition and avoidance, and structural models for clustered PCDH junctions show a linear arrangement in which their long and straight ectodomains form antiparallel overlapped trans complexes. Here, we report all-atom molecular dynamics simulations testing the mechanics of minimalistic adhesive junctions formed by CDH1, DSG2 coupled to DSC1, and PCDHγB4, with systems encompassing up to 3.7 million atoms. Simulations generally predict a favored shearing pathway for the adherens junction model and a two-phased elastic response to tensile forces for the adhesive adherens junction and the desmosome models. Complexes within these junctions first unbend at low tensile force and then become stiff to unbind without unfolding. However, cis interactions in both the CDH1 and DSG2-DSC1 systems dictate varied mechanical responses of individual dimers within the junctions. Conversely, the clustered protocadherin PCDHγB4 junction lacks a distinct two-phased elastic response. Instead, applied tensile force strains trans interactions directly, as there is little unbending of monomers within the junction. Transient intermediates, influenced by new cis interactions, are observed after the main rupture event. We suggest that these collective, complex mechanical responses mediated by cis contacts facilitate distinct functions in robust cell-cell adhesion for classical cadherins and in self-avoidance signaling for clustered PCDHs.
钙黏蛋白基黏附连接和桥粒有助于稳定细胞-细胞连接，并在机械信号转导中发挥额外的功能，而聚集的原钙黏蛋白连接则负责指导神经元回路的组装。由上皮钙黏蛋白 (CDH1) 蛋白形成的黏附连接的结构模型表明，它们的长而弯曲的细胞外结构域排列形成周期性的二维晶格，由尖端到尖端的跨相互作用 (穿过连接点) 和侧向顺式接触稳定。关于桥粒的确切结构知之甚少，但桥粒蛋白 (DSG) 和桥粒胶蛋白 (DSC) 钙黏蛋白也被认为形成有序的连接。相比之下，神经元组织中聚集的原钙黏蛋白 (PCDH) 基细胞-细胞连接被认为负责自我识别和避免，并且聚集的 PCDH 连接的结构模型显示出线性排列，其中它们的长而直的细胞外结构域形成反平行重叠的跨复合物。在这里，我们报告了全原子分子动力学模拟，测试了由 CDH1、与 DSC1 偶联的 DSG2 和 PCDHγB4 形成的最小黏附连接的力学性能，系统包含多达 370 万个原子。模拟通常预测黏附连接模型的剪切途径有利，黏附连接和桥粒模型对拉伸力的弹性响应呈两阶段式。这些连接中的复合物首先在低拉伸力下解开，然后在不展开的情况下变得僵硬而无法解开。然而，CDH1 和 DSG2-DSC1 系统中的顺式相互作用决定了连接中各个二聚体的不同力学响应。相反，聚集的原钙黏蛋白 PCDHγB4 连接缺乏明显的两阶段弹性响应。相反，施加的拉伸力直接应变跨相互作用，因为连接中单体的弯曲很小。在主要断裂事件之后，观察到受新顺式相互作用影响的瞬态中间体。我们认为，这些由顺式接触介导的集体、复杂的力学响应促进了经典钙黏蛋白的稳健细胞-细胞黏附和聚集的 PCDH 的自我避免信号转导的独特功能。
