title: The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region.
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.
authors.affiliation: Max-Planck-Unit for Structural Molecular Biology, Hamburg, FRG.
authors.forename: J
authors.initials: J
authors.lastname: Biernat
authors.forename: E M
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: C
authors.initials: C
authors.lastname: Schröter
authors.forename: B
authors.initials: B
authors.lastname: Lichtenberg-Kraag
authors.forename: B
authors.initials: B
authors.lastname: Steiner
authors.forename: B
authors.initials: B
authors.lastname: Berling
authors.forename: H
authors.initials: H
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Mercken
authors.forename: A
authors.initials: A
authors.lastname: Vandermeeren
authors.forename: M
authors.initials: M
authors.lastname: Goedert
authors.forename: E
authors.initials: E
authors.lastname: Mandelkow
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002417:Cattle; D003001:Cloning, Molecular; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000302:isolation & purification; D010748:Phosphopeptides / Q000302:isolation & purification; D010766:Phosphorylation; D010957:Plasmids; D011392:Proline; D011494:Protein Kinases / Q000378:metabolism*; D012694:Serine; D013552:Swine; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D010748:Phosphopeptides; D016875:tau Proteins; D012694:Serine; D011392:Proline; D011494:Protein Kinases