Ng Tin Long Chris, Hoare Mateo P, Maristany M Julia, Wilde Ellis J, Sneideris Tomas, Huertas Jan, Agbetiameh Belinda K, Furukawa Mona, Joseph Jerelle A, Knowles Tuomas P J, Collepardo-Guevara Rosana, Itzhaki Laura S, Kumita Janet R
Department of Pharmacology, University of Cambridge Tennis Court Road Cambridge CB2 1PD UK
Yusuf Hamied Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK.
Chem Sci. 2025 May 5. doi: 10.1039/d5sc00903k.
The cell's ability to rapidly partition biomolecules into biomolecular condensates is linked to a diverse range of cellular functions. Understanding how the structural attributes of biomolecular condensates are linked with their biological roles can be facilitated by the development of synthetic condensate systems that can be manipulated in a controllable and predictable way. Here, we design and characterise a tuneable synthetic biomolecular condensate platform fusing modular consensus-designed tetratricopeptide repeat (CTPR) proteins to intrinsically-disordered domains. Trends between the CTPR structural attributes and condensate propensity were recapitulated across different experimental conditions and by modelling, demonstrating that the CTPR domain can systematically affect the condensates in a predictable manner. Moreover, we show that incorporating short binding motifs into the CTPR domain results in specific target-protein recruitment into the condensates. Our model system can be rationally designed in a versatile manner to both tune condensate propensity and endow the condensates with new functions.
细胞将生物分子快速分配到生物分子凝聚物中的能力与多种细胞功能相关。通过开发能够以可控和可预测的方式进行操作的合成凝聚物系统，有助于理解生物分子凝聚物的结构属性如何与其生物学作用相联系。在此，我们设计并表征了一个可调节的合成生物分子凝聚物平台，该平台将模块化的一致性设计的四肽重复序列（CTPR）蛋白与内在无序结构域融合。在不同的实验条件下并通过建模，概括了CTPR结构属性与凝聚倾向之间的趋势，表明CTPR结构域能够以可预测的方式系统地影响凝聚物。此外，我们表明将短结合基序纳入CTPR结构域会导致特定靶蛋白被招募到凝聚物中。我们的模型系统可以通过通用方式进行合理设计，既能调节凝聚倾向，又能赋予凝聚物新功能。
