TMAO promotes fibrillization and microtubule assembly activity in the C-terminal repeat region of tau.
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.
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Francesca
F
Scaramozzino
Dylan W
DW
Peterson
Patrick
P
Farmer
J T
JT
Gerig
Donald J
DJ
Graves
John
J
Lew
D019943:Amino Acid Substitution; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008744:Methylamines / Q000378:metabolism / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009454:Neurofibrils / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D008744:Methylamines; D016877:Oxidants; D016875:tau Proteins; D014443:Tyrosine; C005855:trimethyloxamine