Over 300,000 Australians are currently living with a form of dementia which costs $4.9billion annually.  This number is set to increase dramatically as a result of Australia’s aging population. Many forms of dementia arise as a result of neurological protein misfolding leading to the accumulation of toxic aggregates. Associated with these aggregates is the dimeric, intracellular, phospho-serine binding protein, 14-3-3ζ (Fig 1). 14-3-3ζ acts as a molecular chaperone via its ability to suppress the aggregation of target proteins under stress conditions. The nature and mechanism of 14-3-3ζ’s chaperone action are unknown.

The C-terminal extension of 14-3-3ζ, which is important for the protein’s stability, and the amphipathic binding groove, the primary binding region for phosphorylated target proteins, were investigated for their role in 14-3-3ζ’s chaperone action. Neither region was found to be involved in the chaperone action of 14-3-3ζ. Accordingly the dimer interface was investigated using site-directed mutagenesis and a variety of biophysical characterisation. Mutants that showed a disruption of the dimer importantly exhibited increased suppression of target protein aggregation compared to WT 14-3-3ζ, implying that monomeric forms of 14-3-3ζ are more efficient molecular chaperones. From this we hypothesise that the chaperone active site of 14-3-3ζ is the dimer interface which is exposed during dimer dissociation under stress conditions. This is the first physiological role for the monomeric form of 14-3-3ζ to be hypothesised. Characterisation of the chaperone ability of 14-3-3ζ will further our understanding of its role in protein misfolding disorders, and consequently aid us to unravel the complexities of neurological disease.