Department of Physics and Astronomy, California State University, Sacramento, California, United States of America.
Department of Chemistry, California State University, Sacramento, California, United States of America.
PLoS Comput Biol. 2020 Jun 29;16(6):e1007997. doi: 10.1371/journal.pcbi.1007997. eCollection 2020 Jun.
Top-down proteomics has enabled the elucidation of heterogeneous protein complexes with different cofactors, post-translational modifications, and protein membership. This heterogeneity is believed to play a previously unknown role in cellular processes. The different molecular forms of a protein complex have come to be called "complex isoform" or "complexoform". Despite the elucidation of the complexoform, it remains unclear how and whether cellular circuits control the distribution of a complexoform. To help address this issue, we first simulate a generic three-protein complexoform to reveal the control of its distribution by the timing of gene transcription, mRNA translation, and protein transport. Overall, we ran 265 computational experiments: each averaged over 1,000 stochastic simulations. Based on the experiments, we show that genes arranged in a single operon, a cascade, or as two operons all give rise to the different protein composition of complexoform because of timing differences in protein-synthesis order. We also show that changes in the kinetics of expression, protein transport, or protein binding dramatically alter the distribution of the complexoform. Furthermore, both stochastic and transient kinetics control the assembly of the complexoform when the expression and assembly occur concurrently. We test our model against the biological cellulosome system. With biologically relevant rates, we find that the genetic circuitry controls the average final complexoform assembly and the variation in the assembly structure. Our results highlight the importance of both the genetic circuit architecture and kinetics in determining the distribution of a complexoform. Our work has a broad impact on our understanding of non-equilibrium processes in both living and synthetic biological systems.
自上而下的蛋白质组学已经能够阐明具有不同辅助因子、翻译后修饰和蛋白质组成的异质蛋白质复合物。这种异质性被认为在细胞过程中发挥了以前未知的作用。蛋白质复合物的不同分子形式被称为“复合物同工型”或“complexoform”。尽管阐明了 complexoform，但仍不清楚细胞回路如何以及是否控制 complexoform 的分布。为了帮助解决这个问题，我们首先模拟了一个通用的三蛋白 complexoform，以揭示其分布是由基因转录、mRNA 翻译和蛋白质运输的时间控制的。总的来说，我们运行了 265 次计算实验：每个实验平均进行了 1000 次随机模拟。基于这些实验，我们表明，由于蛋白质合成顺序的时间差异，排列在单个操纵子、级联或两个操纵子中的基因都会导致 complexoform 的不同蛋白质组成。我们还表明，表达、蛋白质运输或蛋白质结合的动力学变化会极大地改变 complexoform 的分布。此外，当表达和组装同时发生时，随机和瞬态动力学都会控制 complexoform 的组装。我们将我们的模型与生物细胞体系统进行了比较。在具有生物学相关性的速率下，我们发现遗传电路控制着平均最终 complexoform 组装和组装结构的变化。我们的结果强调了遗传电路结构和动力学在确定 complexoform 分布方面的重要性。我们的工作对我们理解生物和合成生物系统中非平衡过程具有广泛的影响。
