Posttranslational modifications of tau in paired helical filaments.

Paired helical filaments (PHF) are fibrillar structures that accumulate in degenerating neurons of AD brain. We have purified their components, PHF-tau and PHF-smear, and analyzed them protein chemically. PHF-tau is abnormally phosphorylated. Although the characteristic of this phosphorylation is similar to that of fetal tau, its extent is higher in PHF-tau. The additional phosphorylation in PHF-tau may cause its loss of microtubule assembly capacity. Our results on the phosphorylation sites suggested that fetal tau and presumably PHF-tau are in vivo substrates of proline-directed protein kinases. PHF-smear consisted largely of the carboxyl-terminal portion of tau and ubiquitin. The ubiquitin-targeted protein was identified as tau in PHF and the conjugation sites were localized to the microtubule-binding region. It is most likely that abnormally phosphorylated full-length tau (PHF-tau) accumulates as PHF, which is then gradually processed from its amino-terminus and followed by ubiquitination.