Switching of the positive feedback for RAS activation by a concerted function of SOS membrane association domains.
Switching of the positive feedback for RAS activation by a concerted function of SOS membrane association domains.
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DOI：
10.2142/biophysico.13.0_1
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发表时间：
2016
影响因子：
1.5
通讯作者：
Sako Y
中科院分区：
文献类型：
--
作者：
Nakamura Y;Hibino K;Yanagida T;Sako Y
SOS（Son of sevenless）是一种鸟嘌呤核苷酸交换因子，通过激活小GT3-RAS来调节细胞行为。最近的体外研究表明，SOS和GTP结合的RAS活性形式之间的相互作用产生了传播RAS激活的正反馈回路。然而，目前尚不清楚SOS的多个结构域如何有助于调节活细胞中的反馈回路。在这里，我们观察了活细胞中的SOS单分子，以分析SOS行为的动力学和动力学。结果表明，SOS的组蛋白折叠和Grb 2结合结构域协调地在细胞表面产生SOS的中间状态。在正反馈突变体中，中间态的比例降低，表明反馈回路在中间态期间起作用。在正反馈突变体中，识别RAS活性形式的RAF向细胞表面的易位几乎被消除。因此，SOS的多个膜相关结构域的协同功能控制着正反馈回路，这对RAS调控细胞命运决定至关重要。
Son of sevenless (SOS) is a guanine nucleotide exchange factor that regulates cell behavior by activating the small GTPase RAS. Recent in vitro studies have suggested that an interaction between SOS and the GTP-bound active form of RAS generates a positive feedback loop that propagates RAS activation. However, it remains unclear how the multiple domains of SOS contribute to the regulation of the feedback loop in living cells. Here, we observed single molecules of SOS in living cells to analyze the kinetics and dynamics of SOS behavior. The results indicate that the histone fold and Grb2-binding domains of SOS concertedly produce an intermediate state of SOS on the cell surface. The fraction of the intermediated state was reduced in positive feedback mutants, suggesting that the feedback loop functions during the intermediate state. Translocation of RAF, recognizing the active form of RAS, to the cell surface was almost abolished in the positive feedback mutants. Thus, the concerted functions of multiple membrane-associating domains of SOS governed the positive feedback loop, which is crucial for cell fate decision regulated by RAS.