Title

The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.

Journal

Nature

Volume

399

Issue

None

Pages

784-8

Date

1999-06-24

Authors

Lu KP | Zhou XZ | Wulf G | Davies P | Lu PJ

This result confirms previous findings that T231 is an important Cdc2 phosphorylation site in tau, and is also consistent with Pin1 binding mitotically pTau (Fig. 1a) and being sequestered on to PHFs in AD brains, where Cdc2 is upregulated (Fig. 3).

To examine whether Pin1 affects the ability of pTau to bind microtubules, we generated pTau in vitro using purified Cdc2 (refs 17, 18), and determined its ability to bind Taxol-stabilized microtubules with or without Pin1. Although Cdc2 phosphorylation disrupted the ability of tau to bind microtubules; the binding was fully restored by preincubation with Pin1 (Fig. 5a). Furthermore, Pin1 was detected in the fraction of tau-bound microtubules (Fig. 5a). However, no Pin1 was detected in the microtubule fraction if pTau was not added (Fig. 5a), indicating that Pin1 does not bind microtubules directly. Thus, Pin1 binds pTau and restores its ability to bind microtubules.

In contrast, no binding was observed between Pin1 and the nonphosphorylated tau (Fig. 4a), demonstrating that T231 phosphorylation is required for Pin1 binding of tau. To determine whether the WW domain of Pin1 is responsible for binding, the mutant Pin1Y23A was used, which contains a single alanine substitution at the critical Tyr 23 in theWWdomain, resulting in a loss of the phosphoserine-binding activity13. Pin1Y23A showed much less binding to pT231 peptide (Table 1). The residual binding might be due to binding of the pT231 peptide to the much lower affinity isomerase domain of Pin113. These results indicate that the WW domain mediates Pin1 binding to the pT231 sequence of tau.

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