Tunable and reversible drug control of protein production via a self-excising degron.
Tunable and reversible drug control of protein production via a self-excising degron.
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DOI：
10.1038/nchembio.1869
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发表时间：
2015-09
影响因子：
14.8
通讯作者：
Lin MZ
中科院分区：
文献类型：
--
作者：
Chung HK;Jacobs CL;Huo Y;Yang J;Krumm SA;Plemper RK;Tsien RY;Lin MZ
直接化学控制特定蛋白质生产的有效方法将是广泛有用的。我们描述了小分子辅助关闭（SMASh），这是一种将蛋白质与降解决定子融合的技术，该降解决定子在没有药物的情况下会自行去除，留下未标记的蛋白质。临床测试的HCV蛋白酶抑制剂然后可以阻断降解决定子去除，诱导随后合成的蛋白质拷贝的快速降解。SMASh允许在多种哺乳动物细胞类型和酵母中可逆和剂量依赖性地关闭各种蛋白质。我们还使用SMASh赋予药物对RNA病毒的反应性，而这种病毒没有许可的抑制剂。由于SMASh不需要大结构域的永久融合，当需要以最小的结构修饰控制蛋白质产生时，它应该是有用的。此外，由于SMASh仅涉及单一的遗传修饰，并且不依赖于调节蛋白质-蛋白质相互作用，因此应该很容易推广到多种生物学背景。
An effective method for direct chemical control over the production of specific proteins would be widely useful. We describe Small Molecule-Assisted Shutoff (SMASh), a technique in which proteins are fused to a degron that removes itself in the absence of drug, leaving untagged protein. Clinically tested HCV protease inhibitors can then block degron removal, inducing rapid degradation of subsequently synthesized protein copies. SMASh allows reversible and dose-dependent shutoff of various proteins in multiple mammalian cell types and in yeast. We also used SMASh to confer drug responsiveness onto a RNA virus for which no licensed inhibitors exist. As SMASh does not require permanent fusion of a large domain, it should be useful when control over protein production with minimal structural modification is desired. Furthermore, as SMASh only involves a single genetic modification and does not rely on modulating protein-protein interactions, it should be easy to generalize to multiple biological contexts.