Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33602, USA.
Cancer Biology Ph.D Program, University of South Florida, Tampa, FL, 33602, USA.
Nat Commun. 2023 Feb 16;14(1):891. doi: 10.1038/s41467-023-36435-x.
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.
非典型钙黏蛋白 Fat 和 Dachsous 是细胞生长和动物发育的关键调节因子。与形成同质相互作用以分隔细胞的经典钙黏蛋白不同，Fat 和 Dachsous 钙黏蛋白形成异质相互作用，在组织内诱导细胞极性。在这里，我们确定了人同源物 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 的结合域沿每个蛋白的细胞外钙黏蛋白（EC）结构域 1-4 形成扩展界面。生物物理测量表明，Fat4-Dchs1 的亲和力是报道的钙黏蛋白超家族成员中最高的之一，这归因于结构相似的原钙黏蛋白同源二聚体中不存在的广泛盐桥网络。此外，建模表明，异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形成长程、高亲和力的相互作用，以维持平面细胞极性。
