Pin 1
Pin1
is a peptidyl prolyl cis/trans isomerase
Interaction
between tau and Pin1
Tau
proteins and phosphorylation: Pin1 hypothesis
Tau
proteins and phosphorylation: Reactivation of mitotic
mechanisms?
Tau
proteins and phosphorylation: Reactivation of mitotic
mechanisms: A Pin1 role?
Biological
models
NMR spectroscopy also allows for: - •- the identification of groups involved in the interaction between phospho-Thr Tau peptide and WW domain of Pin1
•
- the visualization of the rotamase activity of Pin1
Aggregation of microtubule-associated tau proteins
into filaments is a common feature encountered in Alzheimer's
disease and other neurodegenerative disorders referred
to as tauopathies. Mechanisms leading to this aggregation
are still unknown. However, abnormal phosphorylation
is the major modification of these proteins aggregated
into intracellular filamentous inclusions (1). For
instance, phosphorylation-dependent
antibodies such as TG3 that recognize conformation-dependent
epitopes can visualize phosphorylated tau aggregated
into filaments. TG3 epitope (phosphorylated Thr231)
is expressed in mitotic cells but not in quiescent
cells (2) suggesting that mitotic phosphoepitopes may
lead to conformational changes (2,3). Aborted cell
cycle into pathways leading to cell death is one of
the mechanisms that may contribute to the aggregation
of tau proteins in tauopathies.
Pin1 is a recently characterized human peptidyl-prolyl
cis-trans isomerase
that modulates the assembly, folding, activity
and transport of cellular
proteins (4). It is a mitotic regulator interacting
with a range of proteins
that are phosphorylated prior to cell division
(5). Pin1 recognizes a
specific motif of a phosphorylated Ser or Thr residue
preceding a Pro. Pin1
binds to phospho-Thr231 on tau proteins (6,7).
Very recently, Pin1 was shown
to be involved in tauopathies (6). Pin1 becomes
depleted from the nucleus
within Alzheimer's diseased neurons when it is
redirected to the large
amounts of abnormally phosphorylated tau proteins
that will aggregate into
filaments. This depletion from the nucleus may
ultimately contribute to
neuronal cell death by reactivating the cell cycle.
Conversely, Pin1 could
restore the ability of phosphorylated tau proteins
to bind microtubules and
promote their assembly in vitro. Proline isomerization
may facilitate
Ser/Thr dephosphorylation by phosphatase 2A (8).
REFERENCES
1. Buée L, Bussière T, Buée-Scherrer
V, Delacourte A, Hof PR (2000) Brain
Res Rev, 33: 95-130.
2. Vincent I, Jicha G, Rosado M, Dickson DW (1997)
J Neurosci, 17:
3588-3598.
3. Jicha GA, Lane E, Vincent I, Otvos L, Hoffmann,
R, Davies P (1997) J
Neurochem, 69: 2087-95.
4. Lu KP, Hanes SD, Hunter T (1996) Nature, 380:
544-547.
5. Shen MH, Stukenberg PT, Kirshner MW, Lu KP (1998)
Genes Dev, 12: 706-720.
6. Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP (1999)
Nature, 399: 784-788.
7. Wintjens R, Wieruszeski JM, Drobecq H, Rousselot-Pailley
P, Buée L,
Lippens G, Landrieu I (2001) J Biol Chem, 276 :
25150-25156.
8. Zhou XZ, Kops O, Werner A, Lu P, Shen M, Stoller
G, Kullertz G, Stark M,
Fischer G, Lu KP (2000) Mol Cell, 6: 873-883.
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