This review focusses on pioneering scaffolding examples and elaborates on each parameter influencing the activity of these multi-enzyme complexes. These studies reveal how computational modeling can decipher mechanisms of cross-talk between the p38 and Akt signaling pathways and point to scaffold proteins as central regulators of.
Several successful examples of synthetic protein scaffolds have been reported, yet the optimisation of such multi-enzyme complexes is a multiparametric, and therefore often empirical process. However, scaffolding inhibition can potentiate future kinase activity by redistribution of pathway components, potentially amplifying oncogenic signaling. A particular feature of synthetic protein scaffolds is the control over spatial organisation and enzyme stoichiometry. Enzymes are recruited to this scaffold by fusing them to domains that bind to orthogonal domains in the scaffold. The backbone scaffold is composed of multiple domains that are either separated by linkers or fused to self-assembling proteins. Synthetic protein scaffolds are an advanced way to achieve colocalisation of multiple enzymes in one protein complex. The industrial biotechnology field develops sophisticated methods to mimic natural colocalisation mechanisms to produce increasingly complex bio-based chemicals. Such enzyme colocalisation promotes substrate channelling, enhances the activity of multiple synergistically acting enzymes and avoids the loss of potentially toxic intermediates. As expected, the coexistence region for the mixture shrinks significantly with respect to that of the pure scaffold system due to the depletion of scaffolds (Fig. (3-valency and 2-valency client proteins Fig. Nature relies on complexes of colocated enzymes to efficiently perform multiple catalytic steps. When comparing the phase diagrams of the various clientscaffold mixtures with those of the pure scaffold system.
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