Computational modeling of unphosphorylated CtrA: Cori binding in the Caulobacter cell cycle

Bronson R Weston; John J Tyson; Yang Cao

doi:10.1016/j.isci.2021.103413

Computational modeling of unphosphorylated CtrA: Cori binding in the Caulobacter cell cycle

iScience. 2021 Nov 10;24(12):103413. doi: 10.1016/j.isci.2021.103413. eCollection 2021 Dec 17.

Authors

Bronson R Weston¹, John J Tyson², Yang Cao³

Affiliations

¹ Program in Genetics, Bioinformatics, and Computational Biology, Virginia Tech, Blacksburg, VA, USA.
² Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.
³ Department of Computer Science, Virginia Tech, Blacksburg, VA, USA.

Abstract

In the alphaproteobacterium, Caulobacter crescentus, phosphorylated CtrA (CtrA∼P), a master regulatory protein, binds directly to the chromosome origin (Cori) to inhibit DNA replication. Using a mathematical model of CtrA binding at Cori site [d], we provide computational evidence that CtrA_U can displace CtrA∼P from Cori at the G1-S transition. Investigation of this interaction within a detailed model of the C. crescentus cell cycle suggests that CckA phosphatase may clear Cori of CtrA∼P by altering the [CtrA_U]/[CtrA∼P] ratio rather than by completely depleting CtrA∼P. Model analysis reveals that the mechanism allows for a speedier transition into S phase, stabilizes the timing of chromosome replication under fluctuating rates of CtrA proteolysis, and may contribute to the viability of numerous mutant strains. Overall, these results suggest that CtrA_U enhances the robustness of chromosome replication. More generally, our proposed regulation of CtrA:Cori dynamics may represent a novel motif for molecular signaling in cell physiology.

Keywords: Bacteriology; In silico biology; Mathematical biosciences.