PDF(Pubmed)
Abstract：
Son of Sevenless (SOS) is a Ras guanine nucleotide exchange factor (GEF) that plays a central role in numerous cellular signaling pathways. Like many other signaling molecules, SOS is autoinhibited in the cytosol and activates only after recruitment to the membrane. The mean activation time of individual SOS molecules has recently been measured to be ∼60 s, which is unexpectedly long and seemingly contradictory with cellular signaling timescales, which have been measured to be as fast as several seconds. Here, we rectify this discrepancy using a first-passage time analysis to reconstruct the effective signaling timescale of multiple SOS molecules from their single-molecule activation kinetics. Along with corresponding experimental measurements, this analysis reveals how the functional response time, comprised of many slowly activating molecules, can become substantially faster than the average molecular kinetics. This consequence stems from the enzymatic processivity of SOS in a highly out-of-equilibrium reaction cycle during receptor triggering. Ultimately, rare, early activation events dominate the macroscopic reaction dynamics.
摘要：
Sevenless（SOS）是Ras鸟嘌呤核苷酸交换因子（GEF），在许多细胞信号传导途径中起着核心作用。像许多其他信号分子一样，SOS在胞质溶胶中被自动抑制，并且仅在募集到膜后才激活。最近测得的单个SOS分子的平均激活时间为〜60s，这出乎意料地长，似乎与细胞信号时间尺度相矛盾，被测量为几秒钟。这里,我们通过首次传代时间分析纠正了这种差异,从而从多个SOS分子的单分子激活动力学重建了它们的有效信号时间尺度.连同相应的实验测量，这一分析揭示了功能响应时间，由许多缓慢激活的分子组成，可以变得比平均分子动力学快得多。此结果源于受体触发过程中SOS在高度不平衡的反应循环中的酶促合成能力。最终,罕见,早期激活事件主导宏观反应动力学。
