title: Site-specific pseudophosphorylation modulates the rate of tau filament dissociation.
abstract: Hyperphosphorylation of tau is of fundamental importance for neurofibrillary lesion development in Alzheimer's disease, but the mechanisms through which it acts are not clear. Experiments with pseudophosphorylation mutants of full-length tau protein indicate that incorporation of negative charge into specific sites can modulate the aggregation reaction, and that this occurs by altering the critical concentration of assembly. Here, the kinetic origin of this effect was determined using quantitative electron microscopy methods and pseudophosphorylation mutant T212E in a full-length four-repeat tau background. On the basis of disaggregation rates, decreases in critical concentration resulted primarily from decreases in the dissociation rate constant. The results suggest a mechanism through which site-specific posttranslational modifications can modulate filament accumulation at low free intracellular tau concentrations.
authors.affiliation: Biophysics Program, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Necula
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
mesh_terms: D052160:Benzothiazoles; D006801:Humans; D007700:Kinetics; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C487610:3-(2-hydroxyethyl)-2-(2-((3-(2-hydroxyethyl)-5-methoxy-2-benzothiazolylidene)methyl)-1-butenyl)-5-methoxybenzothiazolium; D052160:Benzothiazoles; D013844:Thiazoles; D016875:tau Proteins; D019000:Phosphotyrosine