Untangling Dynamic Protein Behaviour with Rule-Based Modelling and Sensitivity Analysis

The endoplasmic reticulum (ER) is key to synthesizing mature, functional proteins. Its complex structure consisting of large thin sheets densely packed around the nucleus and elongated tubules reaching throughout the cell is key to its function, and is dynamically regulated in response to cellular signals. CLIMP-63 is the only known protein to play a role in shaping the ER, while also being the target of palmitoylation, one of the few reversible post-translational lipid modifications. In addition to its role in ER structure regulation, CLIMP-63 plays a role as a receptor at the cell surface, where it is known to bind to several ligands. These multiple roles make untangling the regulation of CLIMP-63 abundance and localisation a non-trivial task. We employed rule-based modelling to build a dynamical representation of CLIMP-63 birth, dimerisation, palmitoylation, traficking and degradation. Experimental data in the form of time-dependent radioactive labelling was used to calibrate the model with heuristic optimisation methods. Multiple predictions and hypothesis were generated as to the regulation of CLIMP-63 levels and localisation. Sensitivity Analysis was used on the calibrated model to maximise the extraction of useful knowledge and hypotheses.