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

Andrew Kaplan; Sebastian A Andrei; Anna van Regteren Altena; Tristan Simas; Sara L Banerjee; Nobuo Kato; Nicolas Bisson; Yusuke Higuchi; Christian Ottmann; Alyson E Fournier

doi:10.1016/j.chembiol.2020.02.010

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

Cell Chem Biol. 2020 Jun 18;27(6):657-667.e6. doi: 10.1016/j.chembiol.2020.02.010. Epub 2020 Mar 26.

Authors

Affiliations

¹ Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada. Electronic address: andrew.kaplan@mail.mcgill.ca.
² Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
³ Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada.
⁴ Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Centre de Recherche sur le Cancer, Université Laval, Québec, QC, Canada.
⁵ The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan.
⁶ Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Department of Chemistry, University of Duisburg-Essen, Essen, Germany.
⁷ Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada. Electronic address: alyson.fournier@mcgill.ca.

PMID: 32220335
DOI: 10.1016/j.chembiol.2020.02.010

Abstract

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.

Keywords: 14-3-3; Rap1; axon; polypharmacology; regeneration; spinal cord injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

14-3-3 Proteins / antagonists & inhibitors*
14-3-3 Proteins / isolation & purification
14-3-3 Proteins / metabolism
Animals
Cells, Cultured
Crystallography, X-Ray
Dose-Response Relationship, Drug
Female
Glycosides / chemistry
Glycosides / pharmacology*
Male
Models, Molecular
Molecular Conformation
Neurites / drug effects*
Neurites / metabolism
Neuronal Outgrowth / drug effects
Protein Binding / drug effects
Rats
Rats, Sprague-Dawley
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

14-3-3 Proteins
Glycosides
Small Molecule Libraries
Ywhae protein, rat
fusicoccin

Grants and funding

CIHR/Canada