Zhou Ze-Rui, Wu Man-Sha, Yang Zhenglin, Wu Yuting, Guo Weijie, Li Da-Wei, Qian Ruo-Can, Lu Yi
Key Laboratory for Advanced Materials. East China University of Science and Technology, Shanghai, 200237, P. R. China.
Feringa Nobel Prize Scientist Joint Research Center, Joint International Laboratory for Precision Chemistry. East China University of Science and Technology, Shanghai, 200237, P. R. China.
Nat Commun. 2025 Feb 8;16(1):1464. doi: 10.1038/s41467-025-56758-1.
In living organisms, cells synergistically couple cascade reaction pathways to achieve inter- and intracellular signal transduction by transmembrane protein receptors. The construction and assembly of synthetic receptor analogs that can mimic such biological processes is a central goal of synthetic biochemistry and bionanotechnology to endow receptors with user-defined signal transduction effects. However, designing artificial transmembrane receptors with the desired input, output, and performance parameters are challenging. Here we show that the dimerization of synthetic transmembrane DNA receptors executes a systematically engineered sensing and actuation cascade in response to external molecular signals. The synthetic DNA receptors are composed of three parts, including an extracellular signal reception part, a lipophilic transmembrane anchoring part, and an intracellular signal output part. Upon the input of external signals, the DNA receptors can form dimers on the cell surface triggered by configuration changes, leading to a series of downstream cascade events including communication between donor and recipient cells, gene transcription regulation, protein level control, and cell apoptosis. We believe this work establishes a flexible cell surface engineering strategy that is broadly applicable to implement sophisticated biological functions.
在活生物体中，细胞通过跨膜蛋白受体协同偶联级联反应途径，以实现细胞间和细胞内的信号转导。构建和组装能够模拟此类生物过程的合成受体类似物，是合成生物化学和生物纳米技术的核心目标，旨在赋予受体用户定义的信号转导效应。然而，设计具有所需输入、输出和性能参数的人工跨膜受体具有挑战性。在这里，我们展示了合成跨膜DNA受体的二聚化响应外部分子信号执行了一个系统工程化的传感和驱动级联反应。合成DNA受体由三部分组成，包括细胞外信号接收部分、亲脂性跨膜锚定部分和细胞内信号输出部分。在外部信号输入时，DNA受体可因构象变化在细胞表面形成二聚体，导致一系列下游级联事件，包括供体细胞与受体细胞之间的通讯、基因转录调控、蛋白质水平控制和细胞凋亡。我们相信这项工作建立了一种灵活的细胞表面工程策略，可广泛应用于实现复杂的生物学功能。
