Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, Hong Kong.
HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.
Angew Chem Int Ed Engl. 2022 Aug 22;61(34):e202207319. doi: 10.1002/anie.202207319. Epub 2022 Jul 13.
Synthetic messenger RNA (mRNA) switches are powerful synthetic biological tools that can sense cellular molecules to manipulate cell fate. However, their performances are limited by high output signal noise due to leaky output protein expression. Here, we designed a readout control module that disables protein leakage from generating signal. Aptamer array on the switch guides the inactive output protein to self-assemble into functional assemblies that generate output signal. Leaky protein expression fails to saturate the array, thus produces marginal signal. In this study, we demonstrated that switches with this module exhibit substantially lower signal noise and, consequently, higher input sensitivity and wider output range. Such switches are applicable for different types of input molecules and output proteins. The work here demonstrates a new type of spatially guided protein self-assembly, affording novel synthetic mRNA switches that promise accurate cell manipulation for biomedical applications.
合成信使 RNA（mRNA）开关是强大的合成生物学工具，可感知细胞分子以操纵细胞命运。然而，由于漏出的输出蛋白表达，它们的性能受到高输出信号噪声的限制。在这里，我们设计了一种读出控制模块，可阻止蛋白漏出以产生信号。开关上的适体阵列引导无活性的输出蛋白自组装成功能性组装体，从而产生输出信号。漏出的蛋白表达无法使阵列饱和，因此只会产生微小的信号。在这项研究中，我们证明了具有该模块的开关具有更低的信号噪声，因此具有更高的输入灵敏度和更宽的输出范围。这种开关适用于不同类型的输入分子和输出蛋白。这项工作展示了一种新型的空间引导蛋白自组装，为用于生物医学应用的精确细胞操作提供了新型合成 mRNA 开关。
