De novo engineering of programmable and multi-functional biomolecular condensates for controlled biosynthesis

Wenwen Yu, Ke Jin, Dandan Wang, Nankai Wang, Yangyang Li, Yanfeng Liu, Jianghua Li, Guocheng Du, Xueqin Lv, Jian Chen, Rodrigo Ledesma-Amaro and Long Liu ()
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Wenwen Yu: Jiangnan University
Ke Jin: Jiangnan University
Dandan Wang: Jiangnan University
Nankai Wang: Jiangnan University
Yangyang Li: Jiangnan University
Yanfeng Liu: Jiangnan University
Jianghua Li: Jiangnan University
Guocheng Du: Jiangnan University
Xueqin Lv: Jiangnan University
Jian Chen: Jiangnan University
Rodrigo Ledesma-Amaro: Imperial College London
Long Liu: Jiangnan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract There is a growing interest in the creation of engineered condensates formed via liquid–liquid phase separation (LLPS) to exert precise cellular control in prokaryotes. However, de novo design of cellular condensates to control metabolic flux or protein translation remains a challenge. Here, we present a synthetic condensate platform, generated through the incorporation of artificial, disordered proteins to realize specific functions in Bacillus subtilis. To achieve this, the “stacking blocks” strategy is developed to rationally design a series of LLPS-promoting proteins for programming condensates. Through the targeted recruitment of biomolecules, our investigation demonstrates that cellular condensates effectively sequester biosynthetic pathways. We successfully harness this capability to enhance the biosynthesis of 2’-fucosyllactose by 123.3%. Furthermore, we find that condensates can enhance the translation specificity of tailored enzyme fourfold, and can increase N-acetylmannosamine titer by 75.0%. Collectively, these results lay the foundation for the design of engineered condensates endowed with multifunctional capacities.

Date: 2024
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DOI: 10.1038/s41467-024-52411-5

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