Hyperphosphorylation of tau in PHF

Abstract

Tau in PHF is known to be highly phosphorylated and immunochemical study has indicated the similarity of the phosphorylation between PHF-tau and fetal tau. We have determined the exact phosphorylation sites in both PHF-tau and fetal rat tau by ion-spray mass spectrometry and sequencing of ethanethiol-modified peptides. In PHF-tau, 19 sites have been identified; all the phosphorylation sites except for Ser-262 are localized to the amino- and carboxyl-terminal flanking regions of the microtubule-binding domain. Half of them are shared by fetal tau. Thus, PHF-tau is much more phosphorylated. Whereas most of the sites in fetal tau are proline-directed, half of them in PHF-tau are nonproline-directed. Overall, the hyperphosphorylation of PHF-tau can be considered to consist of fetal-type phosphorylation and additional proline-directed and nonproline-directed phosphorylation. This extraphosphorylation may provide PHF-tau with the unusual characteristics including assembly incompetence.