Communication across membranes controls critical cellular processes and is achieved by receptors translating extracellular signals into selective cytoplasmic responses. While receptor tertiary structures can now be readily characterized, receptor associations into quaternary structures are very challenging to study and their implications in signal transduction remain poorly understood. Here, we report a computational approach for predicting membrane receptor self-associations, and designing receptor oligomers with various quaternary structures and signaling properties. Using this approach, we designed chemokine receptor CXCR4 dimers with reprogrammed stabilities, conformations, and abilities to activate distinct intracellular signaling proteins. In agreement with our predictions, the designed CXCR4s dimerized through distinct conformations and displayed different quaternary structural changes upon activation. Consistent with the active state models, all engineered CXCR4 oligomers activated the G protein Gi, but only a few specific dimer structures also recruited β-arrestins. Overall, we demonstrate that quaternary structures represent an important unforeseen mechanism of receptor biased signaling and reveal the existence of a conformational switch at the dimer interface of several G protein-coupled receptors including CXCR4, mu-Opioid and type-2 Vasopressin receptors that selectively control the activation of G proteins vs β-arrestin-mediated pathways. The approach should prove useful for predicting and designing receptor associations to uncover and reprogram selective cellular signaling functions.

中文翻译：

---

计算设计的 GPCR 四级结构偏向信号通路激活

跨膜通讯控制关键的细胞过程，并通过受体将细胞外信号转化为选择性细胞质反应来实现。虽然现在可以很容易地表征受体三级结构，但受体与四级结构的关联对研究非常具有挑战性，并且它们在信号转导中的意义仍然知之甚少。在这里，我们报告了一种用于预测膜受体自缔合和设计具有各种四元结构和信号传导特性的受体寡聚体的计算方法。使用这种方法，我们设计了具有重编程稳定性、构象和激活不同细胞内信号蛋白的能力的趋化因子受体 CXCR4 二聚体。与我们的预测一致，设计的 CXCR4 通过不同的构象二聚化，并在激活时显示出不同的四元结构变化。与活动状态模型一致，所有工程化的 CXCR4 寡聚体都激活了 G 蛋白 Gi，但只有少数特定的二聚体结构也募集了 β-抑制蛋白。总的来说，我们证明了四级结构代表了一种重要的、不可预见的受体偏向信号机制，并揭示了在几种 G 蛋白偶联受体的二聚体界面上存在构象开关，包括选择性控制的 CXCR4、mu-Apioid 和 2 型加压素受体。 G蛋白的激活与β-抑制蛋白介导的途径。该方法应该证明对预测和设计受体关联以揭示和重新编程选择性细胞信号传导功能有用。