Allosteric autoactivation of SOS and its kinetic mechanism.
Allosteric autoactivation of SOS and its kinetic mechanism.
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DOI：
10.1080/21541248.2019.1601954
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发表时间：
2021-01-01
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影响因子：
--
通讯作者：
Heo, Jongyun
中科院分区：
文献类型：
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作者：
Hoang, Hanh My;Umutesi, Hope Gloria;Heo, Jongyun
SOS（Son of Sevenless）是鸟嘌呤核苷酸交换因子（GEFs）中的一种，可激活Ras。我们发现，SOS的变构域产生SOS进行以前未被认识的自激活动力学。其基本特征是SOS反馈激活的时间依赖性加速与反应引发剂或启动活性Ras。因此，这种机械自激活特征解释了先前仅阐明的概念，即加速SOS激活，随后引发活性Ras，这是由另一种GEF Ras鸟苷酸释放蛋白（RasGRP）产生的作用。有趣的是，从渐进的RasGRP激活到加速的SOS激活的动力学转变被解释为模拟到数字的转换;然而，从自激活动力学的角度来看，这是一个直接的RasGRP介导的SOS自激活的过程。从变构蛋白协同性的角度来看，SOS自激活是一种独特的时间依赖性协同SOS激活，因为它使一个活性SOS能够加速其他SOS的激活，作为时间的函数。这种依赖于时间的SOS协同性不属于经典的稳态蛋白质协同性，其依赖于配体浓度。虽然其滞后或S形饱和曲率是稳态蛋白质协同性的经典标志，但其双曲线饱和图通常代表蛋白质非协同性。我们还发现，SOS自激活扰动先前预测的滞后SOS激活在稳定状态下产生双曲线饱和曲线。我们认为这表明SOS变构通过SOS自激活，协同作用具有时间依赖性，而不是配体浓度依赖性。
Son of Sevenless (SOS), one of guanine nucleotide exchange factors (GEFs), activates Ras. We discovered that the allosteric domain of SOS yields SOS to proceed a previously unrecognized autoactivation kinetics. Its essential feature is a time-dependent acceleration of SOS feedback activation with a reaction initiator or with the priming of active Ras. Thus, this mechanistic autoactivation feature explains the notion, previously only conjectured, of accelerative SOS activation followed by the priming of active Ras, an action produced by another GEF Ras guanyl nucleotide-releasing protein (RasGRP). Intriguingly, the kinetic transition from gradual RasGRP activation to accelerative SOS activation has been interpreted as an analog to digital conversion; however, from the perspective of autoactivation kinetics, it is a process of straightforward RasGRP-mediated SOS autoactivation. From the viewpoint of allosteric protein cooperativity, SOS autoactivation is a unique time-dependent cooperative SOS activation because it enables an active SOS to accelerate activation of other SOS as a function of time. This time-dependent SOS cooperativity does not belong to the classic steady-state protein cooperativity, which depends on ligand concentration. Although its hysteretic or sigmoid-like saturation curvature is a classic hallmark of steady-state protein cooperativity, its hyperbolic saturation figure typically represents protein noncooperativity. We also discovered that SOS autoactivation perturbs the previously predicted hysteresis of SOS activation in a steady state to produce a hyperbolic saturation curve. We interpret this as showing that SOS allostery elicits, through SOS autoactivation, cooperativity uniquely time-dependent but not ligand concentration dependent.