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PubMed: 21882945

Title
Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies.
Journal
Future medicinal chemistry
Volume
3
Issue
None
Pages
1523-37
Date
2011-09-01
Authors
Dickey CA | Gestwicki JE | Kiray J | Koren J | Miyata Y

Evidence 690dfd5ee0
JSON

For example, Hsp90 inhibitors cause degradation of tau and many cancer-related substrates [85].

a(CHEBI:"Hsp90 inhibitor") increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence a6f63caaa0
JSON

Moreover, these compounds were found to prolong binding of Hsp90 to a model substrate, which was sufficient to promote its degradation [142]

a(CHEBI:"Hsp90 inhibitor") increases complex(a(MESH:Proteins), p(FPLX:HSP90)) View Subject | View Object

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complex(a(MESH:Proteins), p(FPLX:HSP90)) increases deg(a(MESH:Proteins)) View Subject | View Object

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Evidence 991362f634
JSON

There are no cures for any tauopathy. Neuroprotective agents, such as acetylcholinesterase inhibitors and NMDA antagonists, have been approved for use in the clinic, based on their ability to slow the rate of cognitive decline in patients with moderate to severe AD (reviewed in [36])

a(CHEBI:"NMDA receptor antagonist") positiveCorrelation bp(GO:cognition) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(PUBCHEM:134222899) positiveCorrelation bp(GO:cognition) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

bp(GO:cognition) positiveCorrelation a(PUBCHEM:134222899) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

bp(GO:cognition) positiveCorrelation a(CHEBI:"NMDA receptor antagonist") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence ae9b4aac69
JSON

Furthermore, recent evidence suggests that tau is essential for the neurotoxicity of amyloid-b, providing a possible link between these classic AD targets and suggesting that reductions in tau levels might be important via multiple, beneficial mechanisms [46–48]

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

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p(HGNC:MAPT) increases path(HBP:neurotoxicity) View Subject | View Object

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Evidence 900802c7e4
JSON

As might be expected given the diverse mechanisms of these compounds, known Hsp70 inhibitors represent a variety of chemical classes, including dihydropyrimidines, adenosine analogs, polyamines and others (Figure 1) [52,63]. Moreover, many of these inhibitors, including methylene blue and MKT-077, have poorly understood mechanisms

a(CHEBI:"methylene blue") decreases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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a(CHEBI:adenosine) decreases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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a(CHEBI:polyamine) decreases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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a(PUBCHEM:1056) decreases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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a(PUBCHEM:6444403) decreases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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Evidence 6c1e8e906d
JSON

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41]

a(HBP:"Phenylthiazolyl-hydrazide") decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:anthraquinone) decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:benzothiazoles) decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:phenothiazines) decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:polyphenol) decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:rhodanine) decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(PUBCHEM:53789478) decreases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence bb1815f0e4
JSON

More recently, there has also been interest in developing compounds, such as celastrol (Figure 1), that selectively disrupt association of co-chaperones with Hsp90 as an alternative way to control chaperone activity [93–96].

a(CHEBI:celastrol) association act(p(FPLX:HSP90)) View Subject | View Object

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act(p(FPLX:HSP90)) association a(CHEBI:celastrol) View Subject | View Object

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Evidence f1ee94dded
JSON

Work on Hsp90 inhibitors benefited from the early discovery of the natural product, geldanamycin, which competes with ATP and induces destabilization of Hsp90-bound proteins [87]

a(CHEBI:geldanamycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

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Evidence cc300e6321
JSON

For example, the Hsp90 inhibitor geldanamycin mimics ADP binding, but also inhibits recruitment of p23, which is a necessary step in client maturation [145].

a(CHEBI:geldanamycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

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a(CHEBI:geldanamycin) decreases complex(p(FPLX:HSP90), p(HGNC:PTGES3)) View Subject | View Object

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Evidence 9b9d3f6718
JSON

Since this discovery, a number of high-affinity analogs, such as 17-AAG, and alternative synthetic scaffolds, including radicicol and PU-H71, have been reported (Figure 1) [85,88]. These compounds bind in either the N-terminal ATP-binding site (e.g., 17-AAG, radicicol and PU-H71) [89] or C-terminal dimerization domain (e.g., novobiocin and A4) [90,91], and they show great promise as both anticancer compounds and research tools for understanding Hsp90 biology

a(CHEBI:novobiocin) directlyIncreases complex(a(CHEBI:novobiocin), p(INTERPRO:"HSP90, C-terminal domain")) View Subject | View Object

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a(CHEBI:novobiocin) directlyDecreases act(p(FPLX:HSP90)) View Subject | View Object

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a(CHEBI:radicicol) directlyIncreases complex(a(CHEBI:radicicol), p(INTERPRO:"Heat shock protein Hsp90, N-terminal")) View Subject | View Object

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a(CHEBI:radicicol) directlyDecreases act(p(FPLX:HSP90)) View Subject | View Object

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a(CHEBI:tanespimycin) directlyIncreases complex(a(CHEBI:tanespimycin), p(INTERPRO:"Heat shock protein Hsp90, N-terminal")) View Subject | View Object

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a(CHEBI:tanespimycin) directlyDecreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:501026) directlyIncreases complex(a(PUBCHEM:501026), p(INTERPRO:"HSP90, C-terminal domain")) View Subject | View Object

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a(PUBCHEM:501026) directlyDecreases act(p(FPLX:HSP90)) View Subject | View Object

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a(PUBCHEM:9549213) directlyIncreases complex(a(PUBCHEM:9549213), p(INTERPRO:"Heat shock protein Hsp90, N-terminal")) View Subject | View Object

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a(PUBCHEM:9549213) directlyDecreases act(p(FPLX:HSP90)) View Subject | View Object

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Evidence 8ea295e6c6
JSON

Using high-throughput screening against the J-protein-stimulated ATPase activity of an Hsp70, we also found polyphenols that selectively block J-stimulated activities by interfering with J-protein recruitment to the Hsp70 complex [72].

a(CHEBI:polyphenol) decreases complex(p(INTERPRO:"Chaperone J-domain superfamily"), p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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Evidence 744f8b5544
JSON

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119].

a(CHEBI:tanespimycin) decreases act(p(FPLX:HSP90)) View Subject | View Object

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a(CHEBI:tanespimycin) decreases p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

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a(CHEBI:tanespimycin) decreases p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

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Evidence 87c9d02b89
JSON

Tauopathies are a family of neurodegenerative disorders characterized by the appearance of aggregates of the microtubule-associating protein, tau.

a(HBP:"Tau aggregates") increases path(MESH:Tauopathies) View Subject | View Object

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Evidence 423eb8d6ef
JSON

The intrinsic ATPase activity of Hsp70 is very weak (~0.2 nmol/μg/min) [60] and, under physiological conditions, it is regulated by cochaperones, including J-proteins and nucleotide exchange factors (NEFs).

a(MESH:"Guanine Nucleotide Exchange Factors") increases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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p(INTERPRO:"Chaperone J-domain superfamily") increases act(p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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Evidence 328403d096
JSON

Briefly, J-proteins cause a conformational change in Hsp70s that accelerates ATP hydrolysis [61], while NEFs facilitate ADP release [62]

a(MESH:"Guanine Nucleotide Exchange Factors") increases a(CHEBI:ADP) View Subject | View Object

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p(INTERPRO:"Chaperone J-domain superfamily") increases rxn(reactants(a(CHEBI:ATP)), products(a(CHEBI:"phosphate(3-)"), a(CHEBI:ADP))) View Subject | View Object

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Evidence 2027353b30
JSON

Importantly, the Hsps are also critical at the end of a protein’s life, as they facilitate turnover by the proteasome system and the clearance of proteotoxic aggregates by autophagy [53]

a(MESH:"Heat-Shock Proteins") increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

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a(MESH:"Heat-Shock Proteins") increases bp(GO:autophagy) View Subject | View Object

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Evidence 0d1b881b54
JSON

Molecular chaperones are abundant and highly conserved proteins that assume an important role in protein quality control

a(MESH:"Molecular Chaperones") association bp(GO:"protein quality control for misfolded or incompletely synthesized proteins") View Subject | View Object

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bp(GO:"protein quality control for misfolded or incompletely synthesized proteins") association a(MESH:"Molecular Chaperones") View Subject | View Object

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Evidence bd3ea876a5
JSON

For example, we found that dihydropyrimidine-based molecules can either force the association of a prokaryotic Hsp70 with its J-protein partner or, with a relatively modest change in chemical structure, related compounds could block this contact [73].

a(PUBCHEM:1056) regulates complex(p(INTERPRO:"Chaperone J-domain superfamily"), p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

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Evidence 874cba085e
JSON

For example, VER-155008 is an ATP-competitive compound developed by structure-guided design [69,70]

a(PUBCHEM:25195348) decreases act(a(MESH:"Adenosine Triphosphatases")) View Subject | View Object

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Evidence 93dd66d89b
JSON

Several members of the chaperone family are upregulated in response to stress and, thus, these factors have been termed heat shock proteins (Hsps)

bp(GO:"cellular response to stress") increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

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Evidence dc3a8e3981
JSON

These proteins are ATP-independent chaperones that undergo homo-oligomerization in response to stress [97,98]

bp(GO:"cellular response to stress") increases a(HBP:"Hsp27 oligomers") View Subject | View Object

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Evidence 0f515ca566
JSON

Recently, our group demonstrated that viral delivery of wild-type Hsp27 into the brains of tau-transgenic mice reduced tau levels and rescued long-term potentiation deficits.

bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:HSPB1) View Subject | View Object

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p(HGNC:HSPB1) decreases p(HGNC:MAPT) View Subject | View Object

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p(HGNC:HSPB1) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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Evidence 6e926748b1
JSON

For example, tau pathology closely correlates to neuron loss and cognitive deficits

bp(GO:cognition) negativeCorrelation path(MESH:Tauopathies) View Subject | View Object

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bp(GO:"neuron death") positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

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path(MESH:Tauopathies) positiveCorrelation bp(GO:"neuron death") View Subject | View Object

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path(MESH:Tauopathies) negativeCorrelation bp(GO:cognition) View Subject | View Object

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Evidence a952cdf6dc
JSON

Interestingly, tau clearance is known to be impaired in the aging brain [45], supporting the idea that diminished quality control might be conducive to certain tauopathies, such as AD, which are linked to aging

bp(GO:aging) negativeCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

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deg(p(HGNC:MAPT)) negativeCorrelation bp(GO:aging) View Subject | View Object

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Evidence 13de5c61d9
JSON

In relation to tau biology, FKBP51 enhances the association of Hsp90 with tau, co-localizes with tau in murine neurons, coimmunoprecipitates with tau in AD tissue samples and increases with age in an AD mouse model [136].

bp(GO:aging) positiveCorrelation p(HGNC:FKBP5) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:FKBP5) increases complex(p(FPLX:HSP90), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

p(HGNC:FKBP5) directlyIncreases complex(p(HGNC:FKBP5), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:FKBP5) positiveCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence f13fca7979
JSON

To allow substrate release, Hsp27 oligomerization is reversible; a process that is regulated, at least in part, by phosphorylation

bp(GO:phosphorylation) regulates a(HBP:"Hsp27 oligomers") View Subject | View Object

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Evidence 8832cdb822
JSON

All proteins, including tau, are subject to extensive regulation by the cellular quality control pathways, which carefully control the balance between protein expression and turnover to maintain healthy protein homeostasis (or proteostasis)

bp(HBP:Proteostasis) regulates p(HGNC:MAPT) View Subject | View Object

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bp(HBP:Proteostasis) regulates a(MESH:Proteins) View Subject | View Object

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Evidence c87d3ae12c
JSON

Alternatively, either Hsp70 or Hsp90 can recruit the ubiquitin E3 ligase, C-terminal Hsp70 interacting protein (CHIP), to degrade the bound substrate [104]

act(p(HGNC:STUB1)) increases bp(GO:"protein catabolic process") View Subject | View Object

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p(FPLX:HSP90) increases act(p(HGNC:STUB1)) View Subject | View Object

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p(INTERPRO:"Heat shock protein 70 family") increases act(p(HGNC:STUB1)) View Subject | View Object

Appears in Networks:

Evidence 4dfdbdaee1
JSON

For example, BAG-2 inhibits client ubiquitination by CHIP by interfering with the interaction between CHIP and E2 ubiquitin-conjugating enzymes [148].

act(p(HGNC:STUB1)) increases bp(GO:"protein ubiquitination") View Subject | View Object

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p(HGNC:BAG2) decreases act(p(HGNC:STUB1)) View Subject | View Object

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p(HGNC:BAG2) decreases bp(GO:"protein ubiquitination") View Subject | View Object

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p(HGNC:BAG2) decreases complex(p(HGNC:STUB1), p(HGNC:UBA2)) View Subject | View Object

Appears in Networks:

Evidence c3b738482a
JSON

In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding

p(HGNC:MAPT) increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

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p(HGNC:PPP2R5B) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:PPP5C) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence fe92ce01ca
JSON

Interestingly, it was recently found that reducing the levels of Akt, another client of the Hsp90/CHIP complex, facilitates tau degradation [123], suggesting a synchronized balance between competing Hsp90 substrates that may be driven, in part, by their relative abundance or susceptibility to Hsp90 binding

deg(p(HGNC:MAPT)) negativeCorrelation p(HGNC:AKT1) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:STUB1)) association p(HGNC:AKT1) View Subject | View Object

Appears in Networks:

p(HGNC:AKT1) association complex(p(FPLX:HSP90), p(HGNC:STUB1)) View Subject | View Object

Appears in Networks:

p(HGNC:AKT1) negativeCorrelation deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 6cfa8cdd75
JSON

During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy

p(HGNC:HSPB1) increases bp(GO:"protein quality control for misfolded or incompletely synthesized proteins") View Subject | View Object

Appears in Networks:

p(HGNC:HSPB1) increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:HSPB1) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) increases bp(GO:"protein quality control for misfolded or incompletely synthesized proteins") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(INTERPRO:"Heat shock protein 70 family") increases bp(GO:"protein quality control for misfolded or incompletely synthesized proteins") View Subject | View Object

Appears in Networks:

p(INTERPRO:"Heat shock protein 70 family") increases bp(GO:"proteasomal protein catabolic process") View Subject | View Object

Appears in Networks:

p(INTERPRO:"Heat shock protein 70 family") increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence ec6e3ded56
JSON

Hsp27 has emerged as a potential target for tau regulation based on early findings that it preferentially binds to phosphorylated and hyperphosphorylated tau and promotes their clearance [125,126]

p(HGNC:HSPB1) directlyIncreases complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:

p(HGNC:HSPB1) directlyIncreases complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Appears in Networks:

complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:

complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(Ph))) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Appears in Networks:

Evidence c223ab4ca4
JSON

However, astrocyte-derived Hsp27 has been shown to promote tau accumulation and Hsp27 associates with tau tangles in a mouse model [127,128], suggesting a more complex relationship

p(HGNC:HSPB1) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

p(HGNC:HSPB1) directlyIncreases complex(a(MESH:"Neurofibrillary Tangles"), p(HGNC:HSPB1)) View Subject | View Object

Appears in Networks:

Evidence 6993ef2217
JSON

Although both Hsp70 and Hsp90 can promote degradation of client proteins, it has recently been shown that, functionally, the Hsp70 complex often dominates triage decisions [85,107,109]

p(FPLX:HSP90) increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:

p(INTERPRO:"Heat shock protein 70 family") increases bp(GO:"protein catabolic process") View Subject | View Object

Appears in Networks:

Evidence d815004054
JSON

Hsp90 was also shown to increase association of tau with microtubules [114]; however, its binding is not well characterized and it is not known whether this is a direct or indirect process

p(FPLX:HSP90) increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 8c5ae11df7
JSON

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118]

p(FPLX:HSP90) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) regulates act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

Evidence 5c018d363d
JSON

Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau

p(FPLX:HSP90) regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) regulates p(HGNC:MAPT, var("?")) View Subject | View Object

Appears in Networks:

Evidence 9863a722f0
JSON

Finally, the FKBP51–Hsp90 complex has been proposed to be responsible for the interaction of tau with phosphatases, helping to restore binding to microtubules [137].

complex(a(MESH:"Protein Phosphatase 2"), p(HGNC:MAPT)) increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

complex(p(FPLX:HSP90), p(HGNC:FKBP5)) increases complex(a(MESH:"Protein Phosphatase 2"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 579bf11044
JSON

In this model,accumulation of an Hsp70–substrate complex (either via treatment with chemical inhibitors or because of intrinsic properties of the substrate) might allow enough time for a degradation factor (e.g., CHIP) to bind and facilitate polyubiquitination.

complex(a(MESH:Proteins), p(HGNC:STUB1), p(INTERPRO:"Heat shock protein 70 family")) positiveCorrelation complex(a(MESH:Proteins), p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

Appears in Networks:

complex(a(MESH:Proteins), p(HGNC:STUB1), p(INTERPRO:"Heat shock protein 70 family")) increases bp(GO:"protein polyubiquitination") View Subject | View Object

Appears in Networks:

complex(a(MESH:Proteins), p(INTERPRO:"Heat shock protein 70 family")) positiveCorrelation complex(a(MESH:Proteins), p(HGNC:STUB1), p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

Appears in Networks:

Evidence 0872392068
JSON

Hsp70 has been shown to both stabilize binding of tau to microtubules [114] and promote its degradation in combination with CHIP [115,116]

p(INTERPRO:"Heat shock protein 70 family") increases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:STUB1), p(INTERPRO:"Heat shock protein 70 family")) increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 29b9f148a1
JSON

In fact, recent work from our group has shown that inhibition of the ATPase activity of Hsp70/Hsc70 promotes proteasomal degradation of tau; whereas activation results in tau accumulation [117]

act(p(INTERPRO:"Heat shock protein 70 family")) increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

act(p(HGNC:HSPA8)) increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 25871921b7
JSON

The fact that Hsp70 inhibitors reduce tau levels without affecting other likely Hsp70 substrates, such as a-synuclein or TDP-43, generally supports the idea that substrates are actively involved in dictating their own fate [117]

act(p(INTERPRO:"Heat shock protein 70 family")) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

Evidence c3c0ef9a97
JSON

Recent structural studies have suggested that Hsp90 functions as a homodimer in which the C-terminal domains of two Hsp90 molecules are in contact at the bottom of the ‘V-shaped’ open conformer

complex(p(FPLX:HSP90), p(FPLX:HSP90)) increases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence 387e8a7166
JSON

This model is consistent with the data that hyperphosphorylated tau appears to be specifically selected for degradation by some chaperone machines, such as the Hsp90–FKBP51 complex, without effects on normal tau [132,136].

complex(p(FPLX:HSP90), p(HGNC:FKBP5)) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:

Evidence a0f2f517aa
JSON

Recently, the co-chaperone FK506-binding protein 51 kDa (FKBP51) has been implicated as a modulator of tau binding to microtubules

p(HGNC:FKBP5) regulates complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence c96ad8927a
JSON

These interactions may be functionally important because silencing FKBP51 reduces tau and phosphorylated-tau levels [136].

p(HGNC:FKBP5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:FKBP5) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

Evidence 5e07ce47d2
JSON

For example, the co-chaperones cdc37, a peptidyl-prolyl cis-trans isomerase (PPIase) family member, and p23 are all critical for the transfer of kinases to Hsp90 and maturation of the active protein [76,105]

p(HGNC:PTGES3) increases complex(a(MESH:"Protein Kinases"), p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

p(HGNC:CDC37) increases complex(a(MESH:"Protein Kinases"), p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence 012f99d38f
JSON

In another example, McClellan et al. showed that von Hippel–Lindau tumor-suppressor protein requires Hsp70 for its folding and degradation, whereas Hsp90 is only required for degradation [149].

complex(p(FPLX:HSP90), p(HGNC:VHL)) increases deg(p(HGNC:VHL)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:VHL), p(INTERPRO:"Heat shock protein 70 family")) increases deg(p(HGNC:VHL)) View Subject | View Object

Appears in Networks:

Evidence c7e48da068
JSON

BAG1 is upregulated in the hippocampus of AD patients [130], where it associates with tau and increases tau levels in cooperation with Hsp70 [131]

p(HGNC:BAG1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

p(HGNC:BAG1) directlyIncreases complex(p(HGNC:BAG1), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

complex(p(HGNC:BAG1), p(INTERPRO:"Heat shock protein 70 family")) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BAG1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence b22c3913fa
JSON

BAG1 silencing decreases tau levels, consistent with a critical role for this co-chaperone in protecting tau from degradation.

p(HGNC:BAG1) decreases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence d481fb9161
JSON

However, another related BAG family member, BAG2, interacts with Hsp70 and tau but, unlike BAG1, assists clearance of phosphorylated tau [132]

p(HGNC:BAG2) directlyIncreases complex(p(HGNC:BAG2), p(HGNC:MAPT), p(INTERPRO:"Heat shock protein 70 family")) View Subject | View Object

Appears in Networks:

p(HGNC:BAG2) association deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Appears in Networks:

deg(p(HGNC:MAPT, pmod(Ph))) association p(HGNC:BAG2) View Subject | View Object

Appears in Networks:

Evidence 91b6353c91
JSON

However, hyperphosphorylated forms of tau are more prone to aggregate, which might decrease their solubility and remove them from normal cycling

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

Evidence eceaa6b247
JSON

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions

p(HGNC:MAPT, pmod(Ph)) regulates complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CDK5)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:GSK3B)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MARK2)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence abec0e9634
JSON

HOP was also required for degradation, indicating that transfer of von Hippel–Lindau from the Hsp70 complex to Hsp90 is a necessary part of its degradation pathway.

complex(p(HGNC:STIP1), p(HGNC:VHL)) increases deg(p(HGNC:VHL)) View Subject | View Object

Appears in Networks:

Evidence a1ad835cda
JSON

As in the case of Hsp70, cochaperones of Hsp90, such as Aha1, cdc37 and TPR domain-containing proteins, regulate its ATPase activity and control its conformational transitions (reviewed in [84]).

p(HGNC:AHSA1) regulates act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

p(HGNC:CDC37) regulates act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

p(INTERPRO:"Tetratricopeptide repeat-containing domain") regulates act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence f6031e78f1
JSON

In addition, Hsp90’s hydrolysis of ATP, which is stimulated by Aha1, facilitates polypeptide release [82,106] and transfer to CHIP or other E3 ligases [107,108]

p(HGNC:AHSA1) increases rxn(reactants(a(CHEBI:ATP)), products(a(CHEBI:"phosphate(3-)"), a(CHEBI:ADP))) View Subject | View Object

Appears in Networks:

p(HGNC:AHSA1) increases complex(a(CHEBI:polypeptide), p(HGNC:STUB1)) View Subject | View Object

Appears in Networks:

Evidence b141058128
JSON

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events.

p(HGNC:CDK5) increases act(p(HGNC:MARK2)) View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B) increases act(p(HGNC:MARK2)) View Subject | View Object

Appears in Networks:

act(p(HGNC:MARK2)) directlyIncreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence 9a415bc593
JSON

The expression of Hsps is regulated by heat shock factor 1 (HSF1), which, under stress conditions, becomes associated with heat shock elements to elevate the transcription of Hsps and other proteins [51].

p(HGNC:HSF1) increases a(MESH:"Heat-Shock Proteins") View Subject | View Object

Appears in Networks:

Evidence 3aa946d2ac
JSON

However, the mechanisms that link HSF1 induction to improved proteostasis are not yet clear

p(HGNC:HSF1) increases bp(HBP:Proteostasis) View Subject | View Object

Appears in Networks:

Evidence 410faaf6ca
JSON

In addition, recent work has demonstrated that Hsc70, the constitutive cytosolic form of Hsp70s, also dynamically regulates the association of tau with microtubules

p(HGNC:HSPA8) regulates complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence a9e6767ff6
JSON

This co-chaperone is of interest in tauopathies because Hsp110 knockout mice show an age-dependent accumulation of phosphorylated tau in the hippocampus [135].

p(HGNC:HSPH1) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 22d96b4bee
JSON

However, under potentially proteotoxic conditions, the post-translational modifications or mutations that damage tau’s affinity for microtubules and favor its aggregation are thought to generate a molecular ‘danger signal’ that specifically alerts the quality control system [112,113].

p(HGNC:MAPT, var("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("?")) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.