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

Andrew Kaplan (Corresponding author)
, Sebastian A. Andrei
, Anna van Regteren Altena
, Tristan Simas
, Sara L. Banerjee
, Nobuo Kato
, Nicolas Bisson
, Yusuke Higuchi
, Christian Ottmann
, Alyson E. Fournier (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

38 Citations (Scopus)

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.

Original language	English
Pages (from-to)	657-667.e6
Number of pages	17
Journal	Cell Chemical Biology
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2020.02.010
Publication status	Published - 18 Jun 2020

Funding

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and ERA -NET-FRQS to A.E.F. and ECHO-STIP grant 717.014.001 from the Netherlands Organization for Scientific Research (NWO) to C.O. A.K. was supported by the Ann and Richard Sievers Neuroscience Award at the Montreal Neurological Institute and a fellowship from the Fonds de Recherche du Québec – Santé. N.B. holds a Canada Research Chair in Cancer Proteomics (Tier 2). S.L.B. is supported by a PROTEO scholarship. Mass spectrometry was performed at the CHU de Québec – Université Laval Proteomics Platform. We thank Erika Wee at the McGill University Advanced BioImaging Facility (ABIF) and Isabel Rambaldi and Brandon Jansonius for technical assistance. We also thank Chloe Song for insight and discussion.

Funders
McGill University
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

14-3-3
axon
polypharmacology
Rap1
regeneration
spinal cord injury

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10.1016/j.chembiol.2020.02.010

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title = "Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth",

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.",

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AU - Kato, Nobuo

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AU - Fournier, Alyson E.

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

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