Tight regulation of signal transduction is required for all healthy cells, and aberrant signaling leads to countless diseases such as cancer and diabetes. Cells detect signals from their environment and use them to make decisions such as whether or when to proliferate. Our results illustrate another complexity in the broad array of control properties that emerge from the physical effects of spatially localizing components of kinase cascades on scaffold proteins.Author Summary: Signal transduction is the science of cellular communication. These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. All rights reserved.Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. In addition, we also discuss methods for the development of a scaffold building block toolbox with different surface properties, which could be adapted for a diversity of biocatalysts requiring alternative microenvironments for function.īiocatalysis Enzyme cascade Immobilization Protein scaffold Self-assembling. We provide detailed methods for the characterization of the protein scaffolds, as well as approaches to load biocatalytic cargo enzymes and test activity of immobilized cascades. In this chapter, we describe methods for the design and production of a self-assembling protein scaffold system for in vitro coimmobilization of biocatalytic cascade enzymes. Additionally, protein scaffolds are versatile, are easily adapted, and remain robust under different reaction conditions. Protein-based scaffolds can be designed as immobilization platforms for biocatalysts, enabling the genetically encoded spatial organization of single enzymes and multistep enzyme cascades. One approach is to immobilize biocatalysts on a solid support, stabilizing the enzymes and providing optimal microenvironments for reaction sequences. To obtain suitable yields of compounds in a cost-effective manner, biocatalytic reaction cascades must be efficient, robust, and self-sufficient. Biocatalysis is emerging as an alternative approach to chemical synthesis of industrially relevant complex molecules.
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