FOM Institute AMOLF, Amsterdam, The Netherlands.
Biophys J. 2012 Mar 7;102(5):1069-78. doi: 10.1016/j.bpj.2012.02.005. Epub 2012 Mar 6.
In many cellular signaling pathways, key components form clusters at the cell membrane. Although much work has focused on the mechanisms behind such cluster formation, the implications for downstream signaling remain poorly understood. Here, motivated by recent experiments, we use particle-based simulation to study a covalent modification network in which the activating component is either clustered or randomly distributed on the membrane. We find that whereas clustering reduces the response of a single-modification network, it can enhance the response of a double-modification network. The reduction is a bulk effect: a cluster presents a smaller effective target to a substrate molecule in the bulk. The enhancement, on the other hand, is a local effect: a cluster promotes the rapid rebinding and second activation of singly activated substrate molecules. As such, the enhancement relies on frequent collisions on a short timescale, leading to an optimal ratio of diffusion to association that agrees with typical measured rates. We complement simulation with analytic results at both the mean-field and first-passage distribution levels. Our results emphasize the importance of spatially resolved models, showing that significant effects of spatial correlations persist even in spatially averaged quantities such as response curves.
在许多细胞信号通路中，关键组件在细胞膜上形成簇。尽管已经有大量工作集中在这种簇形成的机制上，但下游信号的影响仍知之甚少。在这里，受最近实验的启发，我们使用基于粒子的模拟来研究共价修饰网络，其中激活组件在膜上要么是聚集的，要么是随机分布的。我们发现，虽然聚集降低了单修饰网络的响应，但它可以增强双修饰网络的响应。这种减少是一种整体效应：一个簇在体相中呈现出较小的有效靶标给底物分子。另一方面，增强是一种局部效应：簇促进了单激活底物分子的快速再结合和第二次激活。因此，这种增强依赖于短时间内的频繁碰撞，导致扩散和结合的最佳比率与典型的测量速率一致。我们在平均场和首次通过分布水平上用解析结果来补充模拟。我们的结果强调了空间分辨模型的重要性，表明即使在响应曲线等空间平均量中，空间相关的显著影响仍然存在。
