Cell polarity networks are defined by quantitative features of their constituent feedback circuits, which must be tuned to enable robust and stable polarization, while also ensuring that networks remain responsive to dynamically changing cellular states and/or spatial cues during development. Using the PAR polarity network as a model, we demonstrate that these features are enabled by the dimerization of the polarity protein PAR-2 via its N-terminal RING domain. Combining theory and experiment, we show that dimer affinity is optimized to achieve dynamic, selective, and cooperative binding of PAR-2 to the plasma membrane during polarization. Reducing dimerization compromises positive feedback and robustness of polarization. Conversely, enhanced dimerization renders the network less responsive due to kinetic trapping of PAR-2 on internal membranes and reduced sensitivity of PAR-2 to the anterior polarity kinase, aPKC/PKC-3. Thus, our data reveal a key role for a dynamically oligomeric RING domain in optimizing interaction affinities to support a robust and responsive cell polarity network, and highlight how optimization of oligomerization kinetics can serve as a strategy for dynamic and cooperative intracellular targeting.

中文翻译：

---

优化的 PAR-2 RING 二聚化介导协作和选择性膜结合，以实现稳定的细胞极性。


细胞极性网络由其组成反馈电路的定量特征定义，必须对其进行调整以实现稳健且稳定的极化，同时还确保网络在发育过程中保持对动态变化的细胞状态和/或空间线索的响应。使用 PAR 极性网络作为模型，我们证明这些特征是通过极性蛋白 PAR-2 通过其 N 端 RING 结构域的二聚化实现的。结合理论和实验，我们证明二聚体亲和力经过优化，可在极化过程中实现 PAR-2 与质膜的动态、选择性和协同结合。减少二聚化会损害正反馈和极化的稳健性。相反，由于 PAR-2 在内膜上的动力学捕获以及 PAR-2 对前极性激酶 aPKC/PKC-3 的敏感性降低，增强的二聚化使网络的响应性降低。因此，我们的数据揭示了动态寡聚 RING 结构域在优化相互作用亲和力以支持稳健且响应性的细胞极性网络中的关键作用，并强调了寡聚动力学的优化如何可以作为动态和协作细胞内靶向的策略。