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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| Vydané v: | Cell chemical biology Ročník 27; číslo 6; s. 657 |
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| Hlavní autori: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
18.06.2020
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| ISSN: | 2451-9448, 2451-9448 |
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| 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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| AbstractList | 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. 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.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. |
| Author | Bisson, Nicolas Kaplan, Andrew Kato, Nobuo Simas, Tristan Banerjee, Sara L Ottmann, Christian Fournier, Alyson E van Regteren Altena, Anna Andrei, Sebastian A Higuchi, Yusuke |
| Author_xml | – sequence: 1 givenname: Andrew surname: Kaplan fullname: Kaplan, Andrew email: andrew.kaplan@mail.mcgill.ca organization: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada. Electronic address: andrew.kaplan@mail.mcgill.ca – sequence: 2 givenname: Sebastian A surname: Andrei fullname: Andrei, Sebastian A organization: Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands – sequence: 3 givenname: Anna surname: van Regteren Altena fullname: van Regteren Altena, Anna organization: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada – sequence: 4 givenname: Tristan surname: Simas fullname: Simas, Tristan organization: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada – sequence: 5 givenname: Sara L surname: Banerjee fullname: Banerjee, Sara L organization: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Centre de Recherche sur le Cancer, Université Laval, Québec, QC, Canada – sequence: 6 givenname: Nobuo surname: Kato fullname: Kato, Nobuo organization: The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan – sequence: 7 givenname: Nicolas surname: Bisson fullname: Bisson, Nicolas organization: Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Centre de Recherche sur le Cancer, Université Laval, Québec, QC, Canada – sequence: 8 givenname: Yusuke surname: Higuchi fullname: Higuchi, Yusuke organization: The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan – sequence: 9 givenname: Christian surname: Ottmann fullname: Ottmann, Christian organization: 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 – sequence: 10 givenname: Alyson E surname: Fournier fullname: Fournier, Alyson E email: alyson.fournier@mcgill.ca organization: Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada. Electronic address: alyson.fournier@mcgill.ca |
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| Keywords | 14-3-3 spinal cord injury axon regeneration Rap1 polypharmacology |
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| Title | Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth |
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