Department of Chemical Engineering, Sargent Centre for Process Systems Engineering, Imperial College London, London SW7 2AZ, UK.
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
J R Soc Interface. 2023 Feb;20(199):20220510. doi: 10.1098/rsif.2022.0510. Epub 2023 Feb 1.
Biochemical networks are at the heart of cellular information processing. These networks contain distinct facets: (i) processing of information from the environment via cascades/pathways along with network regulation and (ii) modification of substrates in different ways, to confer protein functionality, stability and processing. While many studies focus on these factors individually, how they interact and the consequences for cellular systems behaviour are poorly understood. We develop a systems framework for this purpose by examining the interplay of network regulation (canonical feedback and feed-forward circuits) and multisite modification, as an exemplar of substrate modification. Using computational, analytical and semi-analytical approaches, we reveal distinct and unexpected ways in which the substrate modification and network levels combine and the emergent behaviour arising therefrom. This has important consequences for dissecting the behaviour of specific signalling networks, tracing the origins of systems behaviour, inference of networks from data, robustness/evolvability and multi-level engineering of biomolecular networks. Overall, we repeatedly demonstrate how focusing on only one level (say network regulation) can lead to profoundly misleading conclusions about all these aspects, and reveal a number of important consequences for experimental/theoretical/data-driven interrogations of cellular signalling systems.
生化网络是细胞信息处理的核心。这些网络包含不同的方面：（i）通过级联/途径以及网络调节从环境中处理信息，以及（ii）以不同的方式修饰底物，以赋予蛋白质功能、稳定性和处理能力。虽然许多研究都单独关注这些因素，但它们如何相互作用以及对细胞系统行为的影响还知之甚少。我们通过研究网络调节（经典反馈和前馈电路）和多部位修饰的相互作用，开发了一个系统框架，以此为例来研究底物修饰。我们使用计算、分析和半分析方法，揭示了底物修饰和网络层面组合的独特且出乎意料的方式，以及由此产生的涌现行为。这对于剖析特定信号网络的行为、追踪系统行为的起源、从数据推断网络、鲁棒性/可进化性以及生物分子网络的多层次工程都具有重要意义。总的来说，我们反复证明了仅关注一个层面（例如网络调节）可能会导致对所有这些方面产生严重误导的结论，并揭示了对细胞信号系统进行实验/理论/数据驱动研究的一些重要后果。
