title: Dynamical Localization of DivL and PleC in the Asymmetric Division Cycle of Caulobacter crescentus: A Theoretical Investigation of Alternative Models.
abstract: Cell-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.
authors.affiliation: Graduate Program in Genetics, Bioinformatics and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
authors.forename: Kartik
authors.initials: K
authors.lastname: Subramanian
authors.affiliation: Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Paul
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America; Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tyson
mesh_terms: D016935:Caulobacter crescentus / Q000166:cytology* / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003198:Computer Simulation; D008954:Models, Biological; D062211:Spatio-Temporal Analysis; D013347:Subcellular Fractions / Q000502:physiology* / Q000648:ultrastructure; D014018:Tissue Distribution
chemical_list: D018797:Cell Cycle Proteins