title: Scaffold-mediated nucleation of protein signaling complexes: elementary principles.
abstract: Proteins with multiple binding sites play important roles in cell signaling systems by nucleating protein complexes in which, for example, enzymes and substrates are co-localized. Proteins that specialize in this function are called by a variety names, including adapter, linker and scaffold. Scaffold-mediated nucleation of protein complexes can be either constitutive or induced. Induced nucleation is commonly mediated by a docking site on a scaffold that is activated by phosphorylation. Here, by considering minimalist mathematical models, which recapitulate scaffold effects seen in more mechanistically detailed models, we obtain analytical and numerical results that provide insights into scaffold function. These results elucidate how recruitment of a pair of ligands to a scaffold depends on the concentrations of the ligands, on the binding constants for ligand-scaffold interactions, on binding cooperativity, and on the milieu of the scaffold, as ligand recruitment is affected by competitive ligands and decoy receptors. For the case of a bivalent scaffold, we obtain an expression for the unique scaffold concentration that maximally recruits a pair of monovalent ligands. Through simulations, we demonstrate that a bivalent scaffold can nucleate distinct sets of ligands to equivalent extents when the scaffold is present at different concentrations. Thus, the function of a scaffold can potentially change qualitatively with a change in copy number. We also demonstrate how a scaffold can change the catalytic efficiency of an enzyme and the sensitivity of the rate of reaction to substrate concentration. The results presented here should be useful for understanding scaffold function and for engineering scaffolds to have desired properties.
authors.affiliation: Chinese Academy of Sciences, Max Planck Society Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China. jinyang2004@gmail.com
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
mesh_terms: D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D015530:Nuclear Matrix / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D008024:Ligands