近日，美国加州大学旧金山分校Hana El-Samad小组报道了具有反馈调控功能的从头设计蛋白质开关。2019年8月8日，国际知名学术期刊《自然》发表了这一成果。

研究人员利用degronLOCKR的即插即用特性来实现内源信号通路和合成基因回路的反馈调控。首先，研究人员通过将degronLOCKR与内源性信号分子融合，在酵母交配途径中产生出合成的正负反馈信号，这表明该策略可用于重新连接复杂的内源途径。研究人员接下来评估了在合成基因回路上由degronLOCKR介导的反馈控制，以量化反馈调控回路的反馈能力和操作范围。degronLOCKR蛋白的设计特性使得能够进行简单而合理的修改，从而调整合成回路和交配通路中的反馈行为。将反馈调控设计到活细胞中代表了实现合成生物学的全部潜力中重要的里程碑。更广泛地说，这项工作展示了蛋白质从头设计，在产生可用于生物技术和治疗应用的在细胞中实现复杂合成功能的工具中，存在巨大的且尚未开发的潜力。

据介绍，从头设计的蛋白质作为合成回路的构建模块具有很大的前景，并且可以补充对天然蛋白质的工程化变体的使用。degronLOCKR蛋白就是这样的一种设计产物，这种基于锁定正交的笼子-钥匙蛋白（LOCKR）技术，是一种通过基因编码的短肽引起体内目的蛋白降解的开关。

附：英文原文

Title: Modular and tunable biological feedback control using a de novo protein switch

Author: Andrew H. Ng, Taylor H. Nguyen, Mariana Gmez-Schiavon, Galen Dods, Robert A. Langan, Scott E. Boyken, Jennifer A. Samson, Lucas M. Waldburger, John E. Dueber, David Baker, Hana El-Samad

Issue&Volume:  Volume 572 Issue 7768

Abstract: De novo-designed proteins hold great promise as building blocks for synthetic circuits, and can complement the use of engineered variants of natural proteins. One such designer proteindegronLOCKR, which is based on latching orthogonal cagekey proteins (LOCKR) technologyis a switch that degrades a protein of interest in vivo upon induction by a genetically encoded small peptide. Here we leverage the plug-and-play nature of degronLOCKR to implement feedback control of endogenous signalling pathways and synthetic gene circuits. We first generate synthetic negative and positive feedback in the yeast mating pathway by fusing degronLOCKR to endogenous signalling molecules, illustrating the ease with which this strategy can be used to rewire complex endogenous pathways. We next evaluate feedback control mediated by degronLOCKR on a synthetic gene circuit, to quantify the feedback capabilities and operational range of the feedback control circuit. The designed nature of degronLOCKR proteins enables simple and rational modifications to tune feedback behaviour in both the synthetic circuit and the mating pathway. The ability to engineer feedback control into living cells represents an important milestone in achieving the full potential of synthetic biology. More broadly, this work demonstrates the large and untapped potential of de novo design of proteins for generating tools that implement complex synthetic functionalities in cells for biotechnological and therapeutic applications.

DOI: 10.1038/s41586-019-1425-7

Source: https://www.nature.com/articles/s41586-019-1425-7