The atypical cadherins Fat and Dachsous are key regulators of cell growth and animal development. In contrast to classical cadherins, which form homophilic interactions to segregate cells, Fat and Dachsous cadherins form heterophilic interactions to induce cell polarity within tissues. Here, we determine the co-crystal structure of the human homologs Fat4 and Dachsous1 (Dchs1) to establish the molecular basis for Fat-Dachsous interactions. The binding domains of Fat4 and Dchs1 form an extended interface along extracellular cadherin (EC) domains 1-4 of each protein. Biophysical measurements indicate that Fat4-Dchs1 affinity is among the highest reported for cadherin superfamily members, which is attributed to an extensive network of salt bridges not present in structurally similar protocadherin homodimers. Furthermore, modeling suggests that unusual extracellular phosphorylation modifications directly modulate Fat-Dachsous binding by introducing charged contacts across the interface. Collectively, our analyses reveal how the molecular architecture of Fat4-Dchs1 enables them to form long-range, high-affinity interactions to maintain planar cell polarity.

非典型钙粘蛋白 Fat 和 Dachsous 是细胞生长和动物发育的关键调节剂。与形成嗜同相互作用以分离细胞的经典钙粘蛋白相反，脂肪和 Dachsous 钙粘蛋白形成异嗜相互作用以诱导组织内的细胞极性。在这里，我们确定了人类同系物 Fat4 和 Dachsous1 (Dchs1) 的共晶结构，以建立 Fat-Dachsous 相互作用的分子基础。Fat4 和 Dchs1 的结合域沿着每种蛋白质的细胞外钙粘蛋白 (EC) 域 1-4 形成扩展界面。生物物理测量表明，Fat4-Dchs1 亲和力是钙粘蛋白超家族成员中报告的最高亲和力之一，这归因于结构相似的原钙粘蛋白同二聚体中不存在的广泛盐桥网络。此外，建模表明，不寻常的细胞外磷酸化修饰通过在界面上引入带电接触直接调节 Fat-Dachsous 结合。总的来说，我们的分析揭示了 Fat4-Dchs1 的分子结构如何使它们能够形成远程、高亲和力的相互作用以维持平面细胞极性。