TMAO Promotes Fibrillization and Microtubule Assembly Activity in the C-Terminal Repeat Region of Tau
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- 作者：Francesca Scaramozzino ; Dylan W. Peterson ; Patrick Farmer ; J. T. Gerig ; Donald J. Graves ; and John Lew
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：March 21, 2006
- 年：2006
- 卷：45
- 期：11
- 页码：3684 - 3691
- 全文大小：338K
- 年卷期：v.45,no.11(March 21, 2006)
- ISSN：1520-4995
文摘
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.
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.