Dynamic structural properties of 14-3-3 zeta protein underpin its molecular chaperone action against amorphous protein aggregation

Woodcock JM1, Goodwin KL2, Sandow J3, Coolen C1, Rekas A4 and Carver JA2,5

  1. Centre for Cancer Biology, SA Pathology and University of South Australia, SA.
  2. School of Physical Sciences, University of Adelaide, SA.
  3. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC.
  4. Australian Nuclear and Science Technology Organisation, NSW.
  5. Research School of Chemistry, Australian National University, Canberra, ACT.

The family of 14-3-3 proteins are dimeric phospho-serine binding proteins that function as adaptors with important roles in the regulation of many signaling responses in eukaryotic cells. Less well described, 14-3-3 proteins also exhibit molecular chaperone activity that attenuates the amorphous aggregation of proteins. This property may explain the occurrence of the 14-3-3 zeta isoform in the pathological protein aggregation associated with neurodegenerative conditions including Alzheimer’s and Parkinson’s diseases. To better understand this aspect of 14-3-3 proteins’ function, we have examined the regions of 14-3-3 zeta that play a role in its molecular chaperone action. We determined that neither the flexible C-terminus region nor the amphipathic phospho-serine binding groove contribute to molecular chaperone action. Published studies using mutant forms of 14-3-3 zeta that are engineered to disrupt the dimeric state of the protein suggest that monomeric 14-3-3 zeta represents the chaperone-competent form of the protein. However, our recent results suggest that this is a simplistic view and that the dimer interface of 14-3-3 zeta represents a structurally dynamic region that is involved simultaneously in both 14-3-3 protein dimer formation and molecular chaperone function.