Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics
Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics
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DOI：
10.1126/science.1151153
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发表时间：
2008-03-14
期刊：
影响因子：
56.9
通讯作者：
Lim, Wendell A.
中科院分区：
文献类型：
--
作者：
Bashor, Caleb J.;Helman, Noah C.;Lim, Wendell A.
支架蛋白通过将信号分子物理组装成复合物而将它们连接成线性通路。支架还可以具有作为信号处理中心的更高层次的作用，作为优化信号幅度和定时的反馈回路的目标。我们证明了Ste5支架蛋白可以作为一个平台，系统地重塑酵母交配MAP激酶途径的输出。我们构建了合成的正反馈和负反馈环，通过动态调节招聘的途径调节剂的人工结合位点的Ste5。这些工程电路产生了不同的行为：超灵敏的剂量反应，加速或延迟的反应时间，以及可调的适应。蛋白质支架为细胞反应的重编程提供了一个灵活的平台，并可用于设计具有新的治疗和生物技术功能的细胞。
Scaffold proteins link signaling molecules into linear pathways by physically assembling them into complexes. Scaffolds may also have a higher- order role as signal- processing hubs, serving as the target of feedback loops that optimize signaling amplitude and timing. We demonstrate that the Ste5 scaffold protein can be used as a platform to systematically reshape output of the yeast mating MAP kinase pathway. We constructed synthetic positive- and negative- feedback loops by dynamically regulating recruitment of pathway modulators to an artificial binding site on Ste5. These engineered circuits yielded diverse behaviors: ultrasensitive dose response, accelerated or delayed response times, and tunable adaptation. Protein scaffolds provide a flexible platform for reprogramming cellular responses and could be exploited to engineer cells with novel therapeutic and biotechnological functions.