Department of Physics, Florida State University, Tallahassee, Florida, United States of America.
PLoS Comput Biol. 2012;8(3):e1002427. doi: 10.1371/journal.pcbi.1002427. Epub 2012 Mar 8.
The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors.
细胞因子与其相应受体的细胞外结构域结合后如何通过细胞膜传递信号，其确切机制尚不清楚。受体激活涉及具有 1∶2 化学计量的细胞因子-受体复合物。先前，我们使用瞬态复合物理论计算了初始细胞因子-受体结合形成 1∶1 复合物的速率常数。在这里，我们计算了导致 1∶2 激活复合物形成的结合途径。研究了三种细胞因子系统（生长激素、促红细胞生成素和催乳素），重点是形成 1∶1 复合物后第二个受体分子的细胞外结构域的结合。根据瞬态复合物理论，结合实体的平移和旋转扩散将它们聚集在一起形成瞬态复合物，该复合物具有接近天然的相对分离和取向，但没有短程特定的天然相互作用。随后构象重排导致形成天然复合物。我们发现，从瞬态复合物到 1∶2 天然复合物，两个受体分子之间的相对取向变化在三种细胞因子-受体系统中是相似的。因此，我们提出了一种由 I 类细胞因子激活受体的通用模型，涉及两个受体分子的剪刀样旋转和自旋转的组合。这两种类型的旋转似乎都是必不可少的：剪刀样旋转分离两个受体分子的细胞内结构域，为相关的 Janus 激酶分子腾出空间，而自旋转允许它们正确定向进行转磷酸化。这种激活模型解释了大量的实验观察结果。这里提出的基于瞬态复合物的方法可能为设计拮抗剂提供一种策略，并有助于阐明其他受体的激活机制。
