The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ

14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid beta (A beta) and alpha-synuclein (alpha-syn) form amyloid fibrils in Alzheimer's and Parkinson's diseases, respectively, a process that is intimately linked to the diseases' progression. The 14-3-3 zeta isoform potently inhibited in vitro fibril formation of the 40-amino acid form of A beta (A beta(40)) but had little effect on alpha-syn aggregation. Solution-phase NMR spectroscopy of N-15-labeled A beta(40) and A53T alpha-syn determined that unlabeled 14-3-3 zeta interacted preferentially with hydrophobic regions of A beta(40) (L11-H21 and G29-V40) and alpha-syn (V3-K10 and V40-K60). In both proteins, these regions adopt beta-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3 zeta is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of A beta(40) and alpha-syn. The N-terminal regions of alpha-syn interacting with 14-3-3 zeta correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.