| Abstract
| - Alzheimer's disease most closely correlates with the appearance of the neurofibrillary tangles(NFTs), intracellular fibrous aggregates of the microtubule-associated protein, tau. Under native conditions,tau is an unstructured protein, and its physical characterization has revealed no clues about the three-dimensional structural determinants essential for aggregation or microtubule binding. We have found thatthe natural osmolyte trimethylamine N-oxide (TMAO) induces secondary structure in a C-terminal fragmentof tau (tau187) and greatly promotes both self-aggregation and microtubule (MT) assembly activity. Theseprocesses could be distinguished, however, by a single-amino acid substitution (Tyr310 → Ala), whichseverely inhibited aggregation but had no effect on MT assembly activity. The inability of this mutant toaggregate could be completely reversed by TMAO. We propose a model in which TMAO induces partialorder in tau187, resulting in conformers that may correspond to on-pathway intermediates of eitheraggregation or tau-dependent MT assembly or both. These studies set the stage for future high-resolutionstructural characterization of these intermediates and the basis by which Tyr310 may direct pathologicversus normal tau function.
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