RT Journal Article SR Electronic T1 An important role for periplasmic storage in Pseudomonas aeruginosa copper homeostasis revealed by a combined experimental and computational modeling study JF bioRxiv FD Cold Spring Harbor Laboratory SP 301002 DO 10.1101/301002 A1 Jignesh H. Parmar A1 Julia Quintana A1 David Ramírez A1 Reinhard Laubenbacher A1 José M. Argüello A1 Pedro Mendes YR 2018 UL http://biorxiv.org/content/early/2018/07/13/301002.abstract AB Biological systems require precise copper homeostasis enabling metallation of cuproproteins while preventing metal toxicity. In bacteria, sensing, transport and storage molecules act in coordination to fulfill these roles. However, there is not yet a kinetic schema explaining the system integration. Here, we report a model emerging from experimental and computational approaches that describes the dynamics of copper distribution in Pseudomonas aeruginosa. Based on copper uptake experiments, a minimal kinetic model describes well the copper distribution in the wild type bacteria but is unable to explain the behavior of the mutant strain lacking CopA1, a key Cu+ efflux ATPase. The model was expanded through an iterative hypothesis-driven approach, arriving to a mechanism that considers the induction of compartmental pools and the parallel function of CopA and Cus efflux systems. Model simulations support the presence of a periplasmic copper storage with a crucial role under dyshomeostasis conditions in P. aeruginosa. Importantly, the model predicts not only the interplay of periplasmic and cytoplasmic pools but also the existence of a threshold in the concentration of external copper beyond which cells lose their ability to control copper levels.