He Ren, Albert A Lee, L J Nugent Lew, Joseph B DeGrandchamp, Jay T Groves
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引用次数: 0
摘要
通过 Ras-MAPK 通路传递的信号可呈现开关样激活,这归因于 SOS 将 RasGDP 激活为 RasGTP 的潜在正反馈和双模性。SOS 同时包含催化和异生的 Ras 结合位点,通常的假设是 RasGTP 选择性地异生激活提供了正反馈机制。然而,最近的单分子研究发现,SOS 的催化速率与异构结合位点中 Ras 的核苷酸状态无关,这使人们对其作为一种正反馈机制产生了怀疑。在这里,我们对受体介导的全长 SOS 招募到膜上进行了详细的动力学分析,同时监测了它对 Ras 的催化激活。这些结果以及动力学模型揭示了 SOS 的自动抑制释放步骤,而不是招募或异位激活,是导致 Ras 激活正反馈的基本机制。
Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.
Signaling through the Ras-MAPK pathway can exhibit switch-like activation, which has been attributed to the underlying positive feedback and bimodality in the activation of RasGDP to RasGTP by SOS. SOS contains both catalytic and allosteric Ras binding sites, and a common assumption is that allosteric activation selectively by RasGTP provides the mechanism of positive feedback. However, recent single-molecule studies have revealed that SOS catalytic rates are independent of the nucleotide state of Ras in the allosteric binding site, raising doubt about this as a positive feedback mechanism. Here, we perform detailed kinetic analyses of receptor-mediated recruitment of full-length SOS to the membrane while simultaneously monitoring its catalytic activation of Ras. These results, along with kinetic modeling, expose the autoinhibition release step in SOS, rather than either recruitment or allosteric activation, as the underlying mechanism giving rise to positive feedback in Ras activation.
期刊介绍:
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