Project description:Targeting protein-protein interactions (PPIs) is a promising, but under-exploited, approach in the development of drugs for many indications. 14-3-3 proteins are a family of adaptor molecules with ubiquitous and critical functions in dozens of cell signaling networks. 14-3-3s bind to hundreds of ‘client proteins’ in a stereotyped fashion, altering client protein function, localization and stability. 14-3-3s are especially 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 employ 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 perturb the 14-3-3 interactome through a unique and previously undescribed mechanism involving direct stabilization and inhibition of 14-3-3 PPIs. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases.

2020-03-31 | PXD017317 | Pride

Neurite outgrowth at the biomimetic interface.

Project description: Not available

| S-EPMC3016852 | biostudies-literature

Pharmacological Modulation of Neurite Outgrowth in Human Neural Progenitor Cells by Inhibiting Non-muscle Myosin II.

Project description: Not available

| S-EPMC8484915 | biostudies-literature

Tropomodulins are negative regulators of neurite outgrowth.

Project description: Not available

| S-EPMC3042488 | biostudies-literature