标题： 质膜中Ras纳米簇形成和信号传导的生物物理机制 显示英文标题

标题： Biophysical mechanism for Ras-nanocluster formation and signaling in plasma membrane

摘要： Ras GTPases 是脂质锚定的 G 蛋白，在细胞信号传导过程中起着基础性作用。 免疫金标记 Ras 的电子显微照片显示，膜结合的 Ras 分子会分离成纳米簇域。 已经提出了几种模型，试图获得纳米簇形成的定量描述，但所有模型都依赖于一些假设，例如 Ras 在簇中的比例与 Ras 单体的比例是恒定的，且与表达水平无关（簇/单体比例）。 然而，这一假设与质量作用定律不一致。 在此，我们提出了一种基于膜中 Ras 分子之间短程吸引和长程排斥的 Ras 聚集的生物物理模型。 为了验证该模型，我们进行了蒙特卡洛模拟，并将统计聚集特性与实验数据进行了比较。 我们发现，可以在不假设恒定的簇/单体比例或脂质筏存在的前提下，恢复不同 Ras 表达水平下的实验观察到的聚集现象。 此外，我们的模型对 Ras 纳米簇的信号传递特性做出了预测，以支持 Ras 纳米簇作为高保真信号传递的模拟-数字-模拟转换器的观点。 显示英文摘要

摘要： Ras GTPases are lipid-anchored G proteins which play a fundamental role in cell signaling processes. Electron micrographs of immunogold-labeled Ras have shown that membrane-bound Ras molecules segregate into nanocluster domains. Several models have been developed in attempts to obtain quantitative descriptions of nanocluster formation, but all have relied on assumptions such as a constant, expression-level independent ratio of Ras in clusters to Ras monomers (cluster/monomer ratio). However, this assumption is inconsistent with the law of mass action. Here, we present a biophysical model of Ras clustering based on short-range attraction and long-range repulsion between Ras molecules in the membrane. To test this model, we performed Monte Carlo simulations and compared statistical clustering properties with experimental data. We find that we can recover the experimentally-observed clustering across a range of Ras expression levels, without assuming a constant cluster/monomer ratio or the existence of lipid rafts. In addition, our model makes predictions about the signaling properties of Ras nanoclusters in support of the idea that Ras nanoclusters act as an analog-digital-analog converter for high fidelity signaling.