Dynamics design of a non-natural transcription factor responding to androst-4-ene-3,17-dione

IF 4.4 2区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Synthetic and Systems Biotechnology Pub Date : 2024-04-06 DOI:10.1016/j.synbio.2024.04.001
Ming Zhao , Mengkai Hu , Rumeng Han, Chao Ye, Xiangfei Li, Tianwen Wang, Yan Liu, Zhenglian Xue, Kun Liu
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Abstract

The production of androst-4-ene-3,17-dione (AD) by the steroidal microbial cell factory requires transcription factors (TFs) to participate in metabolic regulation. However, microbial cell factory lacks effective TFs that can respond to AD in its metabolic pathway. Additionally, finding and obtaining natural TFs that specifically respond to AD is a complex and onerous task. In this study, we devised an artificial TF that responds to AD, termed AdT, based on structure-guided molecular dynamics (MD) simulation. According to MD analysis of the conformational changes of AdT after binding to AD, an LBD in which the N- and C-termini exhibited convergence tendencies was used as a microswitch to guide the assembly of a DNA-binding domain lexA, a linker (GGGGS)2, and a transcription activation domain B42 into an artificial TF. As a proof of design, a AD biosensor was designed and constructed in yeast on the basis of the ligand-binding domain (LBD) of hormone receptor. In addition, the transcription factor activity of AdT was increased by 1.44-fold for its variant F320Y. Overall, we created non-natural TF elements for AD microbial cell factory, and expected that the design TF strategy will be applied to running in parallel to the signaling machinery of the host cell.

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响应雄-4-烯-3,17-二酮的非天然转录因子的动力学设计
类固醇微生物细胞工厂生产雄甾-4-烯-3,17-二酮(AD)需要转录因子(TFs)参与代谢调节。然而,微生物细胞工厂缺乏有效的转录因子,无法对其代谢途径中的雄甾-4-烯-3,17-二酮做出反应。此外,寻找和获得对 AD 有特异性反应的天然 TFs 是一项复杂而繁重的任务。在本研究中,我们基于结构引导的分子动力学(MD)模拟,设计了一种能对AD做出反应的人工TF,称为AdT。根据对AdT与AD结合后构象变化的MD分析,我们利用N端和C端表现出趋同趋势的LBD作为微开关,引导DNA结合域lexA、连接子(GGGGS)2和转录激活域B42组装成人工TF。作为设计验证,以激素受体的配体结合结构域(LBD)为基础,在酵母中设计并构建了一个 AD 生物传感器。此外,AdT 的变体 F320Y 的转录因子活性提高了 1.44 倍。总之,我们为AD微生物细胞工厂创造了非天然的转录因子元件,并期望设计的转录因子策略能与宿主细胞的信号机制并行运行。
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来源期刊
Synthetic and Systems Biotechnology
Synthetic and Systems Biotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-
CiteScore
6.90
自引率
12.50%
发文量
90
审稿时长
67 days
期刊介绍: Synthetic and Systems Biotechnology aims to promote the communication of original research in synthetic and systems biology, with strong emphasis on applications towards biotechnology. This journal is a quarterly peer-reviewed journal led by Editor-in-Chief Lixin Zhang. The journal publishes high-quality research; focusing on integrative approaches to enable the understanding and design of biological systems, and research to develop the application of systems and synthetic biology to natural systems. This journal will publish Articles, Short notes, Methods, Mini Reviews, Commentary and Conference reviews.
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