Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth

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, a...

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Published in:Cell chemical biology Vol. 27; no. 6; p. 657
Main Authors: Kaplan, Andrew, Andrei, Sebastian A, van Regteren Altena, Anna, Simas, Tristan, Banerjee, Sara L, Kato, Nobuo, Bisson, Nicolas, Higuchi, Yusuke, Ottmann, Christian, Fournier, Alyson E
Format: Journal Article
Language:English
Published: United States 18.06.2020
Subjects:
14-3-3
spinal cord injury
axon
regeneration
Rap1
polypharmacology
ISSN:2451-9448, 2451-9448
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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.
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ISSN:2451-9448
2451-9448
DOI:10.1016/j.chembiol.2020.02.010