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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,

 

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