Abstract
The cell cycle of Caulobacter crescentus involves the polar morphogenesis and an asymmetric cell division driven by precise interactions and regulations of proteins, which makes Caulobacter an ideal model organism for investigating bacterial cell development and differentiation. The abundance of molecular data accumulated on Caulobacter motivates system biologists to analyze the complex regulatory network of cell cycle via quantitative modeling. In this paper, We propose a comprehensive model to accurately characterize the underlying mechanisms of cell cycle regulation based on the study of: a) chromosome replication and methylation; b) interactive pathways of five master regulatory proteins including DnaA, GcrA, CcrM, CtrA, and SciP, as well as novel consideration of their corresponding mRNAs; c) cell cycle-dependent proteolysis of CtrA through hierarchical protease complexes. The temporal dynamics of our simulation results are able to closely replicate an extensive set of experimental observations and capture the main phenotype of seven mutant strains of Caulobacter crescentus. Collectively, the proposed model can be used to predict phenotypes of other mutant cases, especially for nonviable strains which are hard to cultivate and observe. Moreover, the module of cyclic proteolysis is an efficient tool to study the metabolism of proteins with similar mechanisms.
Highlights
Caulobacter crescentus (C. crescentus) is a model organism for exploring cell development and cell cycle regulation in prokaryotes
We found the complex and redundant regulatory network ensure the robustness of Caulobacter crescentus system because the change of most molecules does not cause immediate mortality, they influence the time points of cell differentiation and division
The overall model and individual modules such as simulating transcriptional regulations and protease complexes can be further extended to the study of cell development in other bacterial species
Summary
Caulobacter crescentus (C. crescentus) is a model organism for exploring cell development and cell cycle regulation in prokaryotes. While the stalked cell immediately initiates chromosome replication and enters the cell cycle, the swarmer cell searches for suitable environments and differentiates into a stalked cell (sw-to-st transition) before entering the cell cycle replication [1]. The timed asymmetric cell progression of C. crescentus is highly regulated by a cell cycledependent regulatory network including four master regulators–DnaA, GcrA, CtrA, and CcrM [2, 3]. DnaA, GcrA, and CtrA are transcriptional factors that control over 200 cell cycleregulated genes in C. crescentus. These proteins form a loop to control each other. DnaA is a conserved DNA replication initiator, activating replication by binding directly with the chromosome origin (Cori) [7].
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