Ras纳米团簇形成的生物物理机制及质膜信号转导
Biophysical mechanism for Ras-nanocluster formation and signaling in plasma membrane
摘要：
Ras GTP酶是一种脂质锚定的G蛋白，在细胞信号转导过程中发挥重要作用。免疫金标记的Ras的电子显微照片显示，膜结合的Ras分子分离成纳米簇域。已经开发了几种模型，试图获得纳米簇形成的定量描述，但都依赖于假设，如一个恒定的，表达水平独立的Ras在集群中的Ras单体的比例（集群/单体比）。然而，这一假设与质量作用定律不一致。在这里，我们提出了一个生物物理模型的基础上的Ras分子在膜中的短程吸引力和长程排斥的Ras集群。为了测试这个模型，我们进行了Monte Carlo模拟，并与实验数据的统计聚类特性进行比较。我们发现，我们可以恢复实验观察到的聚类范围内的Ras表达水平，而不假设一个恒定的集群/单体比或脂筏的存在。此外，我们的模型对Ras纳米团簇的信号传导特性进行了预测，以支持Ras纳米团簇作为高保真信号传导的模拟-数字-模拟转换器的想法。
英文摘要：
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.
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