Nonspecific Electrostatic Interactions between Tau and 14‐3‐3ζ Promote Tau Aggregating

Abstract

Aberrant accumulation of microtubule associated protein tau and formation of amyloid fibrils are pathological hallmarks of neurodegenerative tauopathies. Previous studies have suggested that the scaffolding protein 14‐3‐3ζ promotes tau aggregating by interacting specifically with the pSer324 14‐3‐3ζ‐binding motif within the third microtubule binding repeat. Therefore, the tau/14‐3‐3ζ interaction is a promising drug target for Alzheimer's disease treatment. Indeed, inhibitors of 14‐3‐3/tau interaction have been found to reduce binding of PKA‐phosphorylated tau protein to 14‐3‐3ζ. However, 14‐3‐3ζ has also been shown to promote aggregation of unphosphorylated tau protein, suggesting that nonspecific interactions between tau and 14‐3‐3ζ may be also involved in tau aggregating. In this work, the interactions between tau K18 construct and 14‐3‐3ζ were investigated. We compared the aggregating propensity for three tau species (i.e. WT, pS324, and S324A) in the presence or absence of 14‐3‐3ζ. Although phosphorylation at Ser324 increased the binding affinity of tau K18 to 14‐3‐3ζ, phosphorylation only showed marginal effect on 14‐3‐3ζ mediated tau aggregating. Furthermore, WT and S324A tau proteins showed similar aggregating propensity in the presence of 14‐3‐3ζ. Although 14‐3‐3ζ specific inhibitors reduced the binding affinity of pS324 tau with 14‐3‐3ζ, NMR spectroscopy showed that nonspecific interactions between pS324 tau and 14‐3‐3ζ remained when 14‐3‐3ζ specific inhibitors were present. Our results suggest that nonspecific interactions between tau and 14‐3‐3ζ play an important role in the 14‐3‐3ζ mediated tau aggregating process.Support or Funding InformationThis work was supported by National Natural Science Foundation of China (Grant number: 21603121) and Hubei University of Technology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.