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These findings establish cooperativity, intrinsic PPI affinity, and MG affinity as key parameters governing MG activity and selectivity, providing a framework for the rational design of MGs targeting hub protein interactomes.
The intrinsically disordered protein Tau is highly phosphorylated under pathological conditions, which, among others, results in Tau liquid–liquid phase separation (LLPS), followed by aggregation. The hub protein 14-3-3 regulates Tau protein solubility and prevents LLPS by binding with phosphorylated Tau residues pS214...
14-3-3 Proteins are hub proteins with an extensive interactome of phosphorylated client proteins, making them attractive targets for molecular glues (MGs) that stabilize specific 14-3-3/client protein complexes. However, selectively stabilizing individual 14-3-3 protein-protein interactions (PPIs) remains a key challen...
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