title: Model-Driven Understanding of Palmitoylation Dynamics: Regulated Acylation of the Endoplasmic Reticulum Chaperone Calnexin.
abstract: Cellular functions are largely regulated by reversible post-translational modifications of proteins which act as switches. Amongst these, S-palmitoylation is unique in that it confers hydrophobicity. Due to technical difficulties, the understanding of this modification has lagged behind. To investigate principles underlying dynamics and regulation of palmitoylation, we have here studied a key cellular protein, the ER chaperone calnexin, which requires dual palmitoylation for function. Apprehending the complex inter-conversion between single-, double- and non-palmitoylated species required combining experimental determination of kinetic parameters with extensive mathematical modelling. We found that calnexin, due to the presence of two cooperative sites, becomes stably acylated, which not only confers function but also a remarkable increase in stability. Unexpectedly, stochastic simulations revealed that palmitoylation does not occur soon after synthesis, but many hours later. This prediction guided us to find that phosphorylation actively delays calnexin palmitoylation in resting cells. Altogether this study reveals that cells synthesize 5 times more calnexin than needed under resting condition, most of which is degraded. This unused pool can be mobilized by preventing phosphorylation or increasing the activity of the palmitoyltransferase DHHC6.
authors.affiliation: Laboratory of Computational Systems Biotechnology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Dallavilla
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Abrami
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Sandoz
authors.affiliation: Laboratory of Computational Systems Biotechnology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Savoglidis
authors.affiliation: Laboratory of Computational Systems Biotechnology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Vassily
authors.initials: V
authors.lastname: Hatzimanikatis
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D000215:Acylation / Q000235:genetics*; D037281:Calnexin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation / Q000235:genetics*; D008954:Models, Biological; D034622:RNA Interference
chemical_list: D037281:Calnexin