Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 201210, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
Proc Natl Acad Sci U S A. 2021 Sep 28;118(39). doi: 10.1073/pnas.2022442118.
The Down syndrome cell adhesion molecule (DSCAM) belongs to the immunoglobulin superfamily (IgSF) and plays important roles in neural development. It has a large ectodomain, including 10 Ig-like domains and 6 fibronectin III (FnIII) domains. Previous data have shown that DSCAM can mediate cell adhesion by forming homophilic dimers between cells and contributes to self-avoidance of neurites or neuronal tiling, which is important for neural network formation. However, the organization and assembly of DSCAM at cell adhesion interfaces has not been fully understood. Here we combine electron microscopy and other biophysical methods to characterize the structure of the DSCAM-mediated cell adhesion and generate three-dimensional views of the adhesion interfaces of DSCAM by electron tomography. The results show that mouse DSCAM forms a regular pattern at the adhesion interfaces. The Ig-like domains contribute to both homophilic interactions and assembly of the pattern, and the FnIII domains are crucial for the pattern formation as well as the interaction with the cell membrane. By contrast, no obvious assembly pattern is observed at the adhesion interfaces mediated by mouse DSCAML1 or DSCAMs, suggesting the different structural roles and mechanisms of DSCAMs in mediating cell adhesion and neural network formation.
唐氏综合征细胞黏附分子（DSCAM）属于免疫球蛋白超家族（IgSF），在神经发育中发挥重要作用。它具有一个大的细胞外结构域，包括 10 个 Ig 样结构域和 6 个纤维连接蛋白 III（FnIII）结构域。先前的数据表明，DSCAM 可以通过细胞之间形成同种二聚体来介导细胞黏附，并有助于轴突的自我回避或神经元平铺，这对于神经网络的形成很重要。然而，DSCAM 在细胞黏附界面的组织和组装尚未被充分理解。在这里，我们结合电子显微镜和其他生物物理方法来表征 DSCAM 介导的细胞黏附的结构，并通过电子断层扫描生成 DSCAM 黏附界面的三维视图。结果表明，小鼠 DSCAM 在黏附界面上形成规则的图案。Ig 样结构域有助于同种二聚体相互作用和图案的组装，而 FnIII 结构域对于图案的形成以及与细胞膜的相互作用至关重要。相比之下，在由小鼠 DSCAML1 或 DSCAMs 介导的黏附界面上没有观察到明显的组装图案，这表明 DSCAMs 在介导细胞黏附和神经网络形成中的不同结构作用和机制。
