Distinct Contribution of Peptidyl Prolyl Cis-trans Isomerases to Tau Functions
Some peptidyl prolyl bonds in certain proteins such as tau can exist in two completely distinct cis and trans conformations, whose conversion can be greatly accelerated by peptidyl prolyl cis-trans isomerase (1,2). A increasing body of evidence indicates that the peptidyl prolyl cis-trans isomerization can act as a novel molecular timer to regulate the amplitude and duration of cellular processes (1,2). This new paper by Chambraud et al. reveals an interesting novel role for the peptidyl prolyl cis-trans isomerase FKBP52 in regulating the function of tau, a microtubule-binding protein that plays a major role in the development of Alzheimer disease and related tauopathies.

FKBP52 is a member of the FKBP (FK506-binding protein) family of peptidyl prolyl cis-trans isomerases and has recently been shown to control chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening in the developing spinal cord. Chambraud et al. reported that FKBP52 interacts with tau,...  Read more

Distinct Contribution of Peptidyl Prolyl Cis-trans Isomerases to Tau Functions
Some peptidyl prolyl bonds in certain proteins such as tau can exist in two completely distinct cis and trans conformations, whose conversion can be greatly accelerated by peptidyl prolyl cis-trans isomerase (1,2). A increasing body of evidence indicates that the peptidyl prolyl cis-trans isomerization can act as a novel molecular timer to regulate the amplitude and duration of cellular processes (1,2). This new paper by Chambraud et al. reveals an interesting novel role for the peptidyl prolyl cis-trans isomerase FKBP52 in regulating the function of tau, a microtubule-binding protein that plays a major role in the development of Alzheimer disease and related tauopathies.

FKBP52 is a member of the FKBP (FK506-binding protein) family of peptidyl prolyl cis-trans isomerases and has recently been shown to control chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening in the developing spinal cord. Chambraud et al. reported that FKBP52 interacts with tau, especially when the latter is in its hyperphosphorylated form, and that FKBP52 and tau colocalize in the distal part of the axons of cortical neurons.

Tau functions at two major stages in the brain: during brain development and brain aging. Dynamic tau phosphorylation occurs during embryonic development, which may play an important role in refining or maintaining neuronal structure and function, whereas tau hyperphosphorylation affects tau function and degradation, leading to tangle formation and neurodegeneration in tauopathies (4). Interestingly, Chambraud et al. found that FKBP52 inhibits the ability of recombinant tau to promote microtubule assembly in vitro. Moreover, overexpression of FKBP52 in differentiating PC12 cells prevents tau accumulation and reduces neurite outgrowth. These results demonstrate that FKBP52 has an inhibitory effect on neuronal differentiation/development and suggest that FKBP52 may be a promoting factor of tauopathy. The latter possibility is especially exciting given that FKBP inhibitors, which are clinically used as immunosuppressive drugs, have been shown to have neuroprotective effects.

Strikingly, these effects of FKBP52 on tau are in sharp contrast to those of Pin1, an another, but distinct peptidyl prolyl cis-trans isomerase (5-8). Pin1 binds to and isomerizes the phosphorylated Thr231-Pro motif in tau to restore tau ability to bind microtubules and to promote their assembly (9), to facilitate tau dephosphorylation by PP2A (10,11), and to promote tau degradation (12). The impact of Pin1 on tauopathy and neurodegeneration has been well established. Pin1 is inhibited by multiple mechanisms in the Alzheimer brain in humans, and deletion of Pin1 in mice causes progressive age-dependent tauopathy (2,10). Moreover, postnatal neuronal Pin1 overexpression effectively inhibits the tauopathy phenotype induced by overexpression of wild-type tau in transgenic mice (1,2). These results demonstrate a pivotal role of Pin1 in protecting against tauopathy in Alzheimer disease.

Although both Pin1 and FKBP52 have peptidyl-prolyl isomerase (PPIase) activity and a specific protein-protein interaction domain (2), they seem to have the opposite effects on tau functions. It is not clear why they have such opposite effects on tau. Notably, Pin1 specifically isomerizes only phosphorylated Ser/Thr-Pro motifs and acts only on phosphorylated tau, but FKBP52 has much less activity towards a Ser/Thr-Pro motif after phosphorylation (7), and Chambraud et al. show it can inhibit the function of non-phosphorylated tau. One interesting possibility is that FKBP52 might act directly on non-phosphorylated tau, although its binding to tau seems to be enhanced by tau hyperphosphorylation. Future studies on how FKBP52 regulates tau protein conformation and function, and whether manipulating FKBP52 affects tauopathy in animal models might help offer new insight into tau regulation and provide potential new approaches to inhibit tauopathies.

References:
1. Lu, K. P., Finn, G., Lee, T. H. and Nicholson, L. K. Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 3, 619-629 (2007). Abstract

2. Lu, K. P. and Zhou, X. Z. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8, 904-916 (2007). Abstract

3. Shim, S. et al. Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening. Neuron 64, 471-483 (2009). Abstract

4. Mawal-Dewan, M., Henley, J., Van de Voorde, A., Trojanowski, J. Q. and Lee, V. M. The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases. J Biol Chem 269, 30981-30987 (1994). Abstract

5 Lu, K. P., Hanes, S. D. and Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544-547 (1996). Abstract

6. Lu, P. J., Zhou, X. Z., Shen, M. and Lu, K. P. Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283, 1325-1328 (1999). Abstract

7. Yaffe, M. B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278, 1957-1960 (1997). Abstract

8. Zhou, X. Z., Lu, P. J., Wulf, G. and Lu, K. P. Phosphorylation-dependent prolyl isomerization: a novel signaling regulatory mechanism. Cell Mol Life Sci 56, 788-806 (1999). Abstract

9. Lu, P. J., Wulf, G., Zhou, X. Z., Davies, P. and Lu, K. P. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784-788 (1999). Abstract

10. Liou, Y. C. et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556-561 (2003). Abstract

11. Zhou, X. Z. et al. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol Cell 6, 873-883 (2000). Abstract

12. Lim, J. et al. Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 118, 1877-1889 (2008). Abstract

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View all comments by Kazuhiro Nakamura

The role of FKBPs in neuronal development and protection has been of interest since the discovery that FKBP inhibitors, such as FK506, possess neuroprotective and neuroregenerative qualities, similar to those of cyclosporine A (Sharkey and Butcher, 1994; Giordani et al., 2003; Sosa et al., 2005). FK506 has also been shown to augment the effects of nerve growth factor (NGF) in promoting neurite outgrowth in PC12 cells and rat dorsal root ganglion explants (Lyons et al., 1994). FK506 has also been shown to promote the regeneration of damaged sciatic nerves in vivo (Gold et al., 1995). It was thought that the regenerative powers of FK506 are dependent on the interaction of FKBP52 with the steroid receptor complex in neuronal cells. Disruption of this interaction by addition of FK506 releases the constituent components p23 and HSP90, which activate downstream signaling pathways and the neuroregenerative response (Gold et al., 1999). However, other evidence suggests that FKBP38 could be responsible for both the neuroprotective and neurotrophic properties of FKBP inhibitors (Edlich et...  Read more

The role of FKBPs in neuronal development and protection has been of interest since the discovery that FKBP inhibitors, such as FK506, possess neuroprotective and neuroregenerative qualities, similar to those of cyclosporine A (Sharkey and Butcher, 1994; Giordani et al., 2003; Sosa et al., 2005). FK506 has also been shown to augment the effects of nerve growth factor (NGF) in promoting neurite outgrowth in PC12 cells and rat dorsal root ganglion explants (Lyons et al., 1994). FK506 has also been shown to promote the regeneration of damaged sciatic nerves in vivo (Gold et al., 1995). It was thought that the regenerative powers of FK506 are dependent on the interaction of FKBP52 with the steroid receptor complex in neuronal cells. Disruption of this interaction by addition of FK506 releases the constituent components p23 and HSP90, which activate downstream signaling pathways and the neuroregenerative response (Gold et al., 1999). However, other evidence suggests that FKBP38 could be responsible for both the neuroprotective and neurotrophic properties of FKBP inhibitors (Edlich et al., 2006).

This new study demonstrates the interaction of FKBP52 with tau protein (Chambraud et al., 2010) and may shed new light on the role of FKBP52 in neuroprotection. It remains to be seen which region of FKBP52 is required for binding HP-tau. I find it unlikely that the peptidyl-proline isomerase (PPIase) domain of FKBP52 interacts specifically with hyperphosphorylated tau, since the proline-binding regions of the FKBP PPIase domains lie in a hydrophobic pocket and show a preference for bulky hydrophobic residues (such as leucine or phenylalanine) preceding the proline in peptide substrates (Van Duyne et al., 1993). Pin1, however, uniquely contains a cluster of basic residues within the active site of its PPIase domain and an N-terminal WW-domain, which convey substrate specificity for a phosphorylated serine or threonine residue preceding the proline. The interaction of Pin1 with tau is dependent on phosphorylation of Thr231, an interaction that may be a critical factor in the prevention of Alzheimer disease (Lu et al., 1999, Thorpe et al., 2004).

The contrasting effects of FKBP52 and Pin1 on tau function are illustrated in microtubule polymerization assays. Lu et al. (1999) demonstrated that Pin1 promotes microtubule assembly by promoting the dephosphorylation of p-tau. Chambraud et al., on the other hand, show that addition of FKBP52 to these assays inhibits microtubule assembly. This suggests that the two PPIases exert functionally distinct, rather than degenerate, effects on tau function. The contrasting effects of each protein on the properties of tau suggest that a fine balance of FKBP52 and Pin1 function is required to prevent the onset of disorders such as Alzheimer disease.

References:
Sharkey J, Butcher SP. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature. 1994 Sep 22;371(6495):336-9. Abstract

Giordani F, Benetolli A, Favero-Filho LA, Lima KC, Cestari Junior L, Milani H. Tacrolimus (FK506) reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study. Braz J Med Biol Res. 2003 Apr;36(4):495-502. Abstract

Sosa I, Reyes O, Kuffler DP. Immunosuppressants: neuroprotection and promoting neurological recovery following peripheral nerve and spinal cord lesions. Exp Neurol. 2005 Sep;195(1):7-15. Abstract

Lyons WE, George EB, Dawson TM, Steiner JP, Snyder SH. Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3191-5. Abstract

Gold BG, Katoh K, Storm-Dickerson T. The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve. J Neurosci. 1995 Nov;15(11):7509-16. Abstract

Gold BG, Densmore V, Shou W, Matzuk MM, Gordon HS. Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J Pharmacol Exp Ther. 1999 Jun;289(3):1202-10. Abstract

Edlich F, Weiwad M, Wildemann D, Jarczowski F, Kilka S, Moutty MC, Jahreis G, Lücke C, Schmidt W, Striggow F, Fischer G. The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. J Biol Chem. 2006 May 26;281(21):14961-70. Abstract

Chambraud B, Sardin E, Giustiniani J, Dounane O, Schumacher M, Goedert M, Baulieu EE. A role for FKBP52 in Tau protein function. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2658-63. Abstract

Van Duyne GD, Standaert RF, Karplus PA, Schreiber SL, Clardy J. Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin. J Mol Biol. 1993 Jan 5;229(1):105-24. Abstract

Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999 Jun 24;399(6738):784-8. Abstract

Thorpe JR, Mosaheb S, Hashemzadeh-Bonehi L, Cairns NJ, Kay JE, Morley SJ, Rulten SL. Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Neurobiol Dis. 2004 Nov;17(2):237-49. Abstract

View all comments by Stuart Rulten