近日，美国华盛顿大学教授Dustin J. Maly课题组揭示了蛋白质二聚作用的多输入化学控制，用于编程分级细胞反应。该研究2019年9月9日在线发表在《自然—生物技术》上。

为了增加可编程的翻译后行为的多样性，科学家构建了一个基于单个蛋白接收器的系统，该系统可以集成多种药物输入，包括已批准的疗法。该系统使用一套工程化的方法读取蛋白，并将药物输入转化为多种输出，以提供受体蛋白的可变二聚状态。研究证明，该单受体蛋白结构可用于编程多种细胞反应，包括转录和哺乳动物细胞信号传导的分级和比例双输出控。该工具可以用来滴定Rac和Rho GTPases的竞争活性，以控制细胞形态。该多功能工具集将使研究人员能够对哺乳动物细胞过程进行翻译后编程并设计细胞疗法。

据悉，用于翻译后控制蛋白质功能的化学和光遗传学方法已经能够调节和工程化细胞功能。但是，这些方法大多只提供单输入、单输出控制。

附：英文原文

Title: Multi-input chemical control of protein dimerization for programming graded cellular responses

Author: Glenna Wink Foight, Zhizhi Wang, Cindy T. Wei, Per Jr Greisen, Katrina M. Warner, Daniel Cunningham-Bryant, Keunwan Park, T. J. Brunette, William Sheffler, David Baker, Dustin J. Maly

Issue&Volume: 2019-09-09

Abstract: Chemical and optogenetic methods for post-translationally controlling protein function have enabled modulation and engineering of cellular functions. However, most of these methods only confer single-input, single-output control. To increase the diversity of post-translational behaviors that can be programmed, we built a system based on a single protein receiver that can integrate multiple drug inputs, including approved therapeutics. Our system translates drug inputs into diverse outputs using a suite of engineered reader proteins to provide variable dimerization states of the receiver protein. We show that our single receiver protein architecture can be used to program a variety of cellular responses, including graded and proportional dual-output control of transcription and mammalian cell signaling. We apply our tools to titrate the competing activities of the Rac and Rho GTPases to control cell morphology. Our versatile tool set will enable researchers to post-translationally program mammalian cellular processes and to engineer cell therapies. Clinically approved drugs can be used to control chemically induced dimerization and program mammalian cellular behaviors.

DOI: 10.1038/s41587-019-0242-8

Source:https://www.nature.com/articles/s41587-019-0242-8