The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region.
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.
Biernat
J
J
Max-Planck-Unit for Structural Molecular Biology, Hamburg, FRG.
Mandelkow
E M
EM
Schröter
C
C
Lichtenberg-Kraag
B
B
Steiner
B
B
Berling
B
B
Meyer
H
H
Mercken
M
M
Vandermeeren
A
A
Goedert
M
M
Mandelkow
E
E
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*
D010446:Peptide Fragments; D010748:Phosphopeptides; D016875:tau Proteins; D012694:Serine; D011392:Proline; D011494:Protein Kinases