Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth. Issue 6 (18th June 2020) - Kaplan, Andrew
Summary: Targeting protein-protein interactions (PPIs) is a promising approach in the development of drugs for many indications. 14-3-3 proteins are a family of phosphoprotein-binding molecules with critical functions in dozens of cell signaling networks. 14-3-3s are abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. New semisynthetic FC-A derivatives with improved binding affinity for 14-3-3 complexes have recently been developed. Here, we use a series of screens that identify these compounds as potent inducers of neurite outgrowth through a polypharmacological mechanism. Using proteomics and X-ray crystallography, we discover that these compounds extensively regulate the 14-3-3 interactome by stabilizing specific PPIs, while disrupting others. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases. Graphical Abstract: Highlights: FC-A is a small molecule that modulates 14-3-3 PPIs and induces neurite outgrowth Derivatives with improved potency were identified in a neurite outgrowth screen Interactome analysis reveals regulation of 14-3-3 PPIs enriched in Rap1 network Derivative FC-NCPC can stabilize or competitively inhibit 14-3-3 PPIs Abstract : Kaplan et al. identify a derivative of the small molecule fusicoccin-A (FC-A) that stimulates neurite outgrowth by regulating dozens of protein-protein interactions (PPIs) in the 14-3-3 adaptor protein interactome. This compound, FC-NCPC, bidirectionally stabilizes and inhibits 14-3-3 PPIs enriched within the Rap1 signaling network, suggesting new targets for CNS indications.