PMID- 10090741
OWN - NLM
STAT- MEDLINE
DCOM- 19990419
LR  - 20131121
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 38
IP  - 12
DP  - 1999 Mar 23
TI  - Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also
      protects it against aggregation into Alzheimer paired helical filaments.
PG  - 3549-58
AB  - One of the hallmarks of Alzheimer's disease is the abnormal state of the
      microtubule-associated protein tau in neurons. It is both highly phosphorylated
      and aggregated into paired helical filaments, and it is commonly assumed that the
      hyperphosphorylation of tau causes its detachment from microtubules and promotes 
      its assembly into PHFs. We have studied the relationship between the
      phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its
      assembly into PHFs. The proline-directed kinases MAPK and GSK3 are known to
      phosphorylate most Ser-Pro or Thr-Pro motifs in the regions flanking the repeat
      domain of tau: they induce the reaction with several antibodies diagnostic of
      Alzheimer PHFs, but this type of phosphorylation has only a weak effect on
      tau-microtubule interactions and on PHF assembly. By contrast, MARK and PKA
      phosphorylate several sites within the repeats (notably the KXGS motifs including
      Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates some
      sites in the flanking domains, notably Ser214. This type of phosphorylation
      strongly reduces tau's affinity for microtubules, and at the same time inhibits
      tau's assembly into PHFs. Thus, contrary to expectations, the phosphorylation
      that detaches tau from microtubules does not prime it for PHF assembly, but
      rather inhibits it. Likewise, although the phosphorylation sites on Ser-Pro or
      Thr-Pro motifs are the most prominent ones on Alzheimer PHFs (by antibody
      labeling), they are only weakly inhibitory to PHF assembly. This implies that the
      hyperphosphorylation of tau in Alzheimer's disease is not directly responsible
      for the pathological aggregation into PHFs; on the contrary, phosphorylation
      protects tau against aggregation.
FAU - Schneider, A
AU  - Schneider A
AD  - Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22603
      Hamburg, Germany.
FAU - Biernat, J
AU  - Biernat J
FAU - von Bergen, M
AU  - von Bergen M
FAU - Mandelkow, E
AU  - Mandelkow E
FAU - Mandelkow, E M
AU  - Mandelkow EM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (tau Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.1.- (MARK1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - Alzheimer Disease/*metabolism/pathology
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Humans
MH  - Microtubules/*metabolism/pathology
MH  - Neurofibrillary Tangles/*metabolism/pathology
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Repetitive Sequences, Nucleic Acid
MH  - Serine/metabolism
MH  - tau Proteins/genetics/*metabolism
EDAT- 1999/03/26 00:00
MHDA- 1999/03/26 00:01
CRDT- 1999/03/26 00:00
PHST- 1999/03/26 00:00 [pubmed]
PHST- 1999/03/26 00:01 [medline]
PHST- 1999/03/26 00:00 [entrez]
AID - 10.1021/bi981874p [doi]
AID - bi981874p [pii]
PST - ppublish
SO  - Biochemistry. 1999 Mar 23;38(12):3549-58. doi: 10.1021/bi981874p.