Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth.
14-3-3 Proteins
/ antagonists & inhibitors
Animals
Cells, Cultured
Crystallography, X-Ray
Dose-Response Relationship, Drug
Female
Glycosides
/ chemistry
Male
Models, Molecular
Molecular Conformation
Neurites
/ drug effects
Neuronal Outgrowth
/ drug effects
Protein Binding
/ drug effects
Rats
Rats, Sprague-Dawley
Small Molecule Libraries
/ chemistry
14-3-3
Rap1
axon
polypharmacology
regeneration
spinal cord injury
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
18 06 2020
18 06 2020
Historique:
received:
30
11
2019
revised:
05
02
2020
accepted:
28
02
2020
pubmed:
30
3
2020
medline:
7
7
2021
entrez:
30
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32220335
pii: S2451-9456(20)30074-X
doi: 10.1016/j.chembiol.2020.02.010
pii:
doi:
Substances chimiques
14-3-3 Proteins
0
Glycosides
0
Small Molecule Libraries
0
Ywhae protein, rat
0
fusicoccin
20108-30-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
657-667.e6Subventions
Organisme : CIHR
Pays : Canada
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.