Bayesian modeling reveals metabolite-dependent ultrasensitivity in the cyanobacterial circadian clock

Lu Hong, Danylo Lavrentovich, Archana Chavan, Eugene Leypunskiy, Charles Matthews, Andy LiWang, Eileen Li, Michael Rust, Aaron Dinner

Molecular Systems Biology

pdf url

Abstract

Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near‐24‐h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA—KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide‐bound states of KaiC. We argue that the ultrasensitive stimulus–response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.

Bibtex

@article{Hong2020,
  title = {Bayesian modeling reveals metabolite‐dependent ultrasensitivity in the cyanobacterial circadian clock},
  volume = {16},
  ISSN = {1744-4292},
  url = {http://dx.doi.org/10.15252/msb.20199355},
  DOI = {10.15252/msb.20199355},
  number = {6},
  journal = {Molecular Systems Biology},
  publisher = {Springer Science and Business Media LLC},
  author = {Hong,  Lu and Lavrentovich,  Danylo O and Chavan,  Archana and Leypunskiy,  Eugene and Li,  Eileen and Matthews,  Charles and LiWang,  Andy and Rust,  Michael J and Dinner,  Aaron R},
  year = {2020},
  month = jun,
  abstract = {Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near‐24‐h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA—KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide‐bound states of KaiC. We argue that the ultrasensitive stimulus–response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.}
}