The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region

EMBO J. 1992 Apr;11(4):1593-7.

Abstract

The paired helical filaments (PHFs) of Alzheimer's disease consist mainly of the microtubule-associated protein tau. PHF tau differs from normal human brain tau in that it has a higher Mr and a special state of phosphorylation. However, the protein kinase(s) involved, the phosphorylation sites on tau and the resulting conformational changes are only poorly understood. Here we show that a new monoclonal antibody, AT8, records the PHF-like state of tau in vitro, and we describe a kinase activity that turns normal tau into a PHF-like state. The epitope of AT8 is around residue 200, outside the region of internal repeats and requires the phosphorylation of serines 199 and/or 202. Both of these are followed by a proline, suggesting that the kinase activity belongs to the family of proline-directed kinases. The epitope of AT8 is nearly coincident with that of another phosphorylation-dependent antibody, TAU1 [Binder, L.I., Frankfurter, A. and Rebhun, L. (1985) J. Cell Biol., 101, 1371-1378], but the two are complementary since TAU1 requires a dephosphorylated epitope.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Brain / metabolism
  • Cattle
  • Cloning, Molecular
  • Humans
  • Microtubules / metabolism*
  • Molecular Sequence Data
  • Peptide Fragments / isolation & purification
  • Phosphopeptides / isolation & purification
  • Phosphorylation
  • Plasmids
  • Proline*
  • Protein Kinases / metabolism*
  • Serine*
  • Swine
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Peptide Fragments
  • Phosphopeptides
  • tau Proteins
  • Serine
  • Proline
  • Protein Kinases