Authors: Ananya Sengupta, Josue Liriano, Brian G. Miller, James H. Frederich
Summary: Fusicoccin A (FC) is a diterpene glycoside that stabilizes protein–protein interactions (PPIs) between 14−3−3 adapter proteins and their phosphoprotein interaction partners. Recently, FC has gained attention for its pro-apoptotic and neuroprotective properties in cell culture. Although the exact molecular mechanism(s) is (are) unresolved, 14–3–3 PPIs are central to this activity. With the goal of refining the pharmacology of this chemotype, we conducted a systematic analysis of the structural features that govern FC-induced stabilization of 14–3–3 PPIs utilizing a C-terminal phosphorylation recognition motif. This study confirmed that a C-terminal amino acid with a small alkyl group is required for the interaction of FC at canonical C-terminal 14–3–3 PPI interfaces. Using bioinformatics, this structural insight was leveraged to assemble a database of 119 candidate 14–3–3 PPIs that can serve as targets for FC. This group includes a subset of proteins with experimentally determined C-terminal phosphosites that have not been explored as potential targets of FC.
Source: ACS Chemical Biology, 2020