Quantitative effect of scaffold abundance on signal propagation.
Quantitative effect of scaffold abundance on signal propagation.
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DOI：
10.1038/msb.2009.73
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发表时间：
2009
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
--
作者：
蛋白质支架将信号通路的多个组分聚集在一起，从而促进信号沿着共同的物理“骨架”沿着传播。支架在天然信号通路中发挥着重要作用，并为合成电路提供了一个有前途的平台。为了更好地理解支架如何定量地影响信号传输，我们对酵母交配途径进行了体内敏感性分析，以广泛的支架Ste5丰度扰动。我们的测量结果表明，信号通量表现出对支架浓度的双相依赖性，并且改变支架结合伴侣的量重塑这种双相依赖性。出乎意料的是，Ste5的野生型水平比最大化信号通量所需的最佳水平低10倍。这种次优配置可能是一种权衡，因为增加Ste5表达促进了交配途径的基线激活。此外，在Ste5的次优水平下操作可以提供调节灵活性，因为上调或下调Ste5表达直接调节下游表型应答。我们的定量分析揭示了基于支架的模块的性能权衡，并定义了在合成途径中实施分子支架的工程挑战。
Protein scaffolds bring together multiple components of a signalling pathway, thereby promoting signal propagation along a common physical ‘backbone'. Scaffolds play a prominent role in natural signalling pathways and provide a promising platform for synthetic circuits. To better understand how scaffolding quantitatively affects signal transmission, we conducted an in vivo sensitivity analysis of the yeast mating pathway to a broad range of perturbations in the abundance of the scaffold Ste5. Our measurements show that signal throughput exhibits a biphasic dependence on scaffold concentration and that altering the amount of scaffold binding partners reshapes this biphasic dependence. Unexpectedly, the wild-type level of Ste5 is ∼10-fold below the optimum needed to maximize signal throughput. This sub-optimal configuration may be a tradeoff as increasing Ste5 expression promotes baseline activation of the mating pathway. Furthermore, operating at a sub-optimal level of Ste5 may provide regulatory flexibility as tuning Ste5 expression up or down directly modulates the downstream phenotypic response. Our quantitative analysis reveals performance tradeoffs in scaffold-based modules and defines engineering challenges for implementing molecular scaffolds in synthetic pathways.
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