TMAO promotes fibrillization and microtubule assembly activity in the C-terminal repeat region of tau

被引：67

作者：

Scaramozzino, F

Peterson, DW

Farmer, P

Gerig, JT

Graves, DJ

Lew, J

机构：

[1] Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara

[2] Department of Chemistry and Biochemistry, University of California, Santa Barbara

来源：

BIOCHEMISTRY | 2006年 / 45卷 / 11期

关键词：

D O I：

10.1021/bi052167g

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 that the natural osmolyte trimethylamine N-oxide (TMAO) induces secondary structure in a C-terminal fragment of tau (tau187) and greatly promotes both self-aggregation and microtubule (MT) assembly activity. These processes could be distinguished, however, by a single-amino acid substitution (Tyr310 → Ala), which severely inhibited aggregation but had no effect on MT assembly activity. The inability of this mutant to aggregate could be completely reversed by TMAO. We propose a model in which TMAO induces partial order in tau187, resulting in conformers that may correspond to on-pathway intermediates of either aggregation or tau-dependent MT assembly or both. These studies set the stage for future high-resolution structural characterization of these intermediates and the basis by which Tyr310 may direct pathologic versus normal tau function. © 2006 American Chemical Society.

引用

页码：3684 / 3691

页数：8

共 53 条

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