Cadherin superfamily members play a critical role in differential adhesion during neurodevelopment, and their disruption has been linked to several neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19), a member of the δ-protocadherin subfamily of cadherins, cause a unique form of epilepsy called PCDH19 clustering epilepsy. While PCDH19 and other non-clustered δ-protocadherins form multimers with other members of the cadherin superfamily to alter adhesiveness, the specific protein surfaces responsible for these interactions are unknown. Only portions of the PCDH19 extracellular domain structure had been solved previously. Here, we present a structure of the missing segment from zebrafish Protocadherin-19 (Pcdh19) and create a complete ectodomain model. This model shows the structural environment for 97% of disease-causing missense mutations and reveals two potential surfaces for intermolecular interactions that could modify Pcdh19's adhesive strength and specificity.

钙粘蛋白超家族成员在神经发育过程中的差异粘附中起关键作用，并且它们的破坏与几种神经发育障碍有关。protocadherin -19 ( PCDH19)的突变) 是钙粘蛋白 δ-原钙粘蛋白亚家族的成员，它会导致一种独特的癫痫形式，称为 PCDH19 丛集性癫痫。虽然 PCDH19 和其他非聚集 δ-原钙粘蛋白与钙粘蛋白超家族的其他成员形成多聚体以改变粘附性，但导致这些相互作用的特定蛋白质表面尚不清楚。之前仅解决了部分 PCDH19 胞外结构域结构。在这里，我们展示了斑马鱼 Protocadherin-19 (Pcdh19) 缺失片段的结构，并创建了一个完整的胞外域模型。该模型显示了 97% 的致病错义突变的结构环境，并揭示了分子间相互作用的两个潜在表面，这些表面可以改变 Pcdh19 的粘附强度和特异性。