Phosphorylation potential and chemical fluxes govern the biological performance of multiple PdP cycles

TL;DR

This study develops a kinetic and thermodynamic model of the G2/M transition in fission yeast, highlighting how phosphorylation energy and chemical fluxes influence bistability, sensitivity, and robustness of cell cycle regulation.

Contribution

It introduces a novel thermodynamic analysis of phosphorylation energy and chemical fluxes in regulating cell cycle transitions, emphasizing their stabilizing roles.

Findings

Phosphorylation energy shapes response curves of key regulators.

Chemical fluxes stabilize Cdc2 activity against energy fluctuations.

Free energy influences bistability and noise levels in the circuit.

Abstract

Fission yeast G2/M transition is regulated by a biochemical reaction networks which contains four components: Cdc13, Cdc2, Wee1, and Cdc25. This circuit is characterized by the ultrasensitive responses of Wee1 or Cdc25 to Cdc13/Cdc2 activity, and the bistability of Cdc2 activation. Previous work has shown that this bistability is governed by phosphorylation energy. In this article, we developed the kinetic model of this circuit and conducted further thermodynamic analysis on the role of phosphorylation energy (&[Delta]G). We showed that level &[Delta]G shapes the response curves of Wee1 or Cdc25 to Cdc2 and governs the intrinsic noise level of Cdc2 activity. More importantly, the mutually antagonistic chemical fluxes around the PdP cycles in G2/M circuit were shown to act as a stabilizer of Cdc2 activity against &[Delta]G fluctuations. These results suggests the fundamental role of free energy and chemical fluxes on the sensitivity, bistability and robustness of G2/M transition.