Dynamic Transition States of ErbB1 Phosphorylation Predicted by Spatial Stochastic Modeling

Meghan McCabe Pryor, Shalini T. Low-Nam, Ádám M. Halász, Diane S. Lidke, Bridget S. Wilson, Jeremy S. Edwards
2013 Biophysical Journal  
ErbB1 overexpression is strongly linked to carcinogenesis, motivating better understanding of erbB1 dimerization and activation. Recent single-particle-tracking data have provided improved measures of dimer lifetimes and strong evidence that transient receptor coconfinement promotes repeated interactions between erbB1 monomers. Here, spatial stochastic simulations explore the potential impact of these parameters on erbB1 phosphorylation kinetics. This rule-based mathematical model incorporates
more » ... tructural evidence for conformational flux of the erbB1 extracellular domains, as well as asymmetrical orientation of erbB1 cytoplasmic kinase domains during dimerization. The asymmetric dimer model considers the theoretical consequences of restricted transactivation of erbB1 receptors within a dimer, where the N-lobe of one monomer docks with the C-lobe of the second monomer and triggers its catalytic activity. The dynamic nature of the erbB1 phosphorylation state is shown by monitoring activation states of individual monomers as they diffuse, bind, and rebind after ligand addition. The model reveals the complex interplay between interacting liganded and nonliganded species and the influence of their distribution and abundance within features of the membrane landscape.
doi:10.1016/j.bpj.2013.07.056 pmid:24048005 pmcid:PMC3785885 fatcat:pbkpm4hszbeuvbznglsqnnea24