TMAO promotes fibrillization and microtubule assembly activity in the C-terminal repeat region of tau.
Biochemistry
; 45(11): 3684-91, 2006 Mar 21.
Article
en En
| MEDLINE
| ID: mdl-16533051
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 that the natural osmolyte trimethylamine N-oxide (TMAO) induces secondary structure in a C-terminal fragment of tau (tau(187)) and greatly promotes both self-aggregation and microtubule (MT) assembly activity. These processes could be distinguished, however, by a single-amino acid substitution (Tyr(310) --> 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 tau(187), 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 Tyr(310) may direct pathologic versus normal tau function.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxidantes
/
Proteínas tau
/
Metilaminas
/
Microtúbulos
/
Neurofibrillas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Biochemistry
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos