Subramanian, KartikPaul, Mark R.Tyson, John J.2016-12-092016-12-092015-07-011553-734Xhttp://hdl.handle.net/10919/73620Cell-fate asymmetry in the predivisional cell of Caulobacter crescentus requires that the regulatory protein DivL localizes to the new pole of the cell where it up-regulates CckA kinase, resulting in a gradient of CtrA~P across the cell. In the preceding stage of the cell cycle (the “stalked” cell), DivL is localized uniformly along the cell membrane and maintained in an inactive form by DivK~P. It is unclear how DivL overcomes inhibition by DivK~P in the predivisional cell simply by changing its location to the new pole. It has been suggested that co-localization of DivL with PleC phosphatase at the new pole is essential to DivL’s activity there. However, there are contrasting views on whether the bifunctional enzyme, PleC, acts as a kinase or phosphatase at the new pole. To explore these ambiguities, we formulated a mathematical model of the spatiotemporal distributions of DivL, PleC and associated proteins (DivJ, DivK, CckA, and CtrA) during the asymmetric division cycle of a Caulobacter cell. By varying localization profiles of DivL and PleC in our model, we show how the physiologically observed spatial distributions of these proteins are essential for the transition from a stalked cell to a predivisional cell. Our simulations suggest that PleC is a kinase in predivisional cells, and that, by sequestering DivK~P, the kinase form of PleC enables DivL to be reactivated at the new pole. Hence, co-localization of PleC kinase and DivL is essential to establishing cellular asymmetry. Our simulations reproduce the experimentally observed spatial distribution and phosphorylation status of CtrA in wild-type and mutant cells. Based on the model, we explore novel combinations of mutant alleles, making predictions that can be tested experimentally.? - ? (27) page(s)Creative Commons Attribution 4.0 InternationalBiochemical Research MethodsMathematical & Computational BiologyBiochemistry & Molecular BiologyBACTERIAL-CELL-CYCLEPOLAR LOCALIZATIONRESPONSE REGULATORDNA-REPLICATIONHISTIDINE KINASETEMPORAL CONTROLSINORHIZOBIUM-MELILOTICHROMOSOME SEGREGATIONALPHA-PROTEOBACTERIAPROTEIN LOCALIZATIONArticle - Refereedhttps://doi.org/10.1371/journal.pcbi.1004348117