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

Kaplan A, Andrei SA, van Regteren Altena A, Simas T, Banerjee SL, Kato N, Bisson N, Higuchi Y, Ottmann C, Fournier AE
Cell Chem Biol 27 657-667.e6 (2020)
Related entries: 6qds, 6qdt, 6qdu

Cited: 13 times
EuropePMC logo PMID: 32220335

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.

Reviews citing this publication (5)

  1. The Surprising Story of Fusicoccin: A Wilt-Inducing Phytotoxin, a Tool in Plant Physiology and a 14-3-3-Targeted Drug. Marra M, Camoni L, Visconti S, Fiorillo A, Evidente A. Biomolecules 11 1393 (2021)
  2. 14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases. Pair FS, Yacoubian TA. Trends Pharmacol Sci 42 226-238 (2021)
  3. Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins. Giusto E, Yacoubian TA, Greggio E, Civiero L. NPJ Parkinsons Dis 7 85 (2021)
  4. Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein-Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases. Li F, Aljahdali IAM, Ling X. Int J Mol Sci 23 6206 (2022)
  5. Protein-protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction. Rui H, Ashton KS, Min J, Wang C, Potts PR. RSC Chem Biol 4 192-215 (2023)

Articles citing this publication (8)

  1. Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms. Gogl G, Tugaeva KV, Eberling P, Kostmann C, Trave G, Sluchanko NN. Nat Commun 12 1677 (2021)
  2. Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products. Wolter M, de Vink P, Neves JF, Srdanović S, Higuchi Y, Kato N, Wilson A, Landrieu I, Brunsveld L, Ottmann C. J Am Chem Soc 142 11772-11783 (2020)
  3. Targeting the Surface of the Protein 14-3-3 by Ultrasmall (1.5 nm) Gold Nanoparticles Carrying the Specific Peptide CRaf. Ruks T, Loza K, Heggen M, Ottmann C, Bayer P, Beuck C, Epple M. Chembiochem 22 1456-1463 (2021)
  4. Genetic encoding of 3-nitro-tyrosine reveals the impacts of 14-3-3 nitration on client binding and dephosphorylation. Zhu P, Nguyen KT, Estelle AB, Sluchanko NN, Mehl RA, Cooley RB. Protein Sci 32 e4574 (2023)
  5. A new soaking procedure for X-ray crystallographic structural determination of protein-peptide complexes. Ballone A, Lau RA, Zweipfenning FPA, Ottmann C. Acta Crystallogr F Struct Biol Commun 76 501-507 (2020)
  6. 007 (x2)-3-3: 14-3-3 Targeted Compounds as Double Agents. Gannon M, Yacoubian TA. Trends Pharmacol Sci 41 431-433 (2020)
  7. Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme. Huang JH, Lv JM, Xiao LY, Xu Q, Lin FL, Wang GQ, Chen GD, Qin SY, Hu D, Gao H. Beilstein J Org Chem 18 1396-1402 (2022)
  8. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments. Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR. J Am Chem Soc 145 20328-20343 (2023)


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