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.
Scaramozzino
Francesca
F
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Peterson
Dylan W
DW
Farmer
Patrick
P
Gerig
J T
JT
Graves
Donald J
DJ
Lew
John
J
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