Potential Role of a Bistable Histidine Kinase Switch in the Asymmetric Division Cycle of Caulobacter crescentus

The free-living aquatic bacterium, Caulobacter crescentus, exhibits two different morphologies during its life cycle. The morphological change from swarmer cell to stalked cell is a result of changes of function of two bi-functional histidine kinases, PleC and CckA. Here, we describe a detailed molecular mechanism by which the function of PleC changes between phosphatase and kinase state. By mathematical modeling of our proposed molecular interactions, we derive conditions under which PleC, CckA and its response regulators exhibit bistable behavior, thus providing a scenario for robust switching between swarmer and stalked states. Our simulations are in reasonable agreement with in vitro and in vivo experimental observations of wild type and mutant phenotypes. According to our model, the kinase form of PleC is essential for the swarmer-to-stalked transition and to prevent premature development of the swarmer pole. Based on our results, we reconcile some published experimental observations and suggest novel mutants to test our predictions.Author Summary: Recent evidence suggests that the transition of PleC from phosphatase to kinase is induced by its own substrate, DivK. Based on experimental clues, we propose a molecular mechanism to explain this substrate-induced conformational change in PleC. The general principles of thermodynamics, enzyme-substrate reactions and the Monod-Wyman-Changeux model of allostery motivate the elementary chemical reactions proposed in our model. Formulating our hypothesis in terms of nonlinear ordinary differential equations, we show that the PleC transition could function as a bistable switch. Although initial experimental studies have suggested that the primary role of PleC is as a phosphatase, our simulations show that the PleC kinase form is relevant for the correct temporal regulation of the Caulobacter cell cycle.