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p(FPLX:HSP90)

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Entity

Name
HSP90
Namespace
FPLX
Namespace Version
20180917
Namespace URL
https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns

Appears in Networks 11

A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. v1.0.0

The Biology of Proteostasis in Aging and Disease v1.0.0

A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways v1.0.0

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing v1.0.0

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies v1.0.0

Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies v1.0.0

Activation and regulation of the inflammasomes v1.0.0

Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity v1.0.0

Molecular Chaperone Functions in Protein Folding and Proteostasis v1.0.0

Molecular chaperones and proteostasis regulation during redox imbalance v1.0.0

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes v1.0.0

In-Edges 82

complex(p(FPLX:HSP90), p(HGNC:PTGES3)) hasComponent p(FPLX:HSP90) View Subject | View Object

Appears in Networks:

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

The ATP-dependent chaperones are comprised of the 5 HSP90s, 17 HSP70s, 14 HSP60s, 6 ER-specific, and 8 MITO-specific Hsp100/AAA+ ATPases, respectively. PubMed:25437566

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

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

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

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

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

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

ATP hydrolysisis essential for the chaperone activity of HSP70 and HSP90, causing conformational changes that result in substrate binding (11). PubMed:25784053

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bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

Additionally, an investigation of chaperone and cochaperone gene expression in young (36±4 years of age) and aged (73 ±4 years of age) human brain tissue revealed that of 332 genes examined, 101 are significantly repressed with age, including HSP70, HSP40, HSP90, and TRiC genes (113). Furthermore, 62 chaperone genes, including several small HSPs, were found to be significantly induced, likely as a result of the cellular response to accumulating protein damage with age (113). PubMed:25784053

Appears in Networks:
Annotations
Cell Ontology (CL)
motor neuron

complex(p(FPLX:HSP90), p(HGNC:POLR3A)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:RPAP3)) hasComponent p(FPLX:HSP90) View Subject | View Object

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

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complex(p(FPLX:HSP90), p(HGNC:URI1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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

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

Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 . PubMed:30116051

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

The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 . PubMed:30116051

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a(PUBCHEM:46216556) decreases act(p(FPLX:HSP90)) View Subject | View Object

Another HSP90 inhibitor, HSP990, has shown promise in lowering Htt aggregates and improving motor performance in two mouse models of HD 225 . PubMed:30116051

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

For example, the Hsp90 inhibitor geldanamycin mimics ADP binding, but also inhibits recruitment of p23, which is a necessary step in client maturation [145]. PubMed:21882945

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

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]. PubMed:21882945

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

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] PubMed:21882945

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

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 PubMed:21882945

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

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 PubMed:21882945

Appears in Networks:

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

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 PubMed:21882945

Appears in Networks:

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

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]. PubMed:21882945

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

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 PubMed:21882945

Appears in Networks:

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

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 PubMed:21882945

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

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

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

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

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 PubMed:21882945

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

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

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complex(p(FPLX:HSP90), p(HGNC:PPID)) hasComponent p(FPLX:HSP90) View Subject | View Object

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

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]). PubMed:21882945

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

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]). PubMed:21882945

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

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]). PubMed:21882945

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complex(p(FPLX:HSP90), p(HGNC:FKBP4)) hasComponent p(FPLX:HSP90) View Subject | View Object

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a(CHEBI:"withaferin A") decreases act(p(FPLX:HSP90)) View Subject | View Object

The Cdc37/Hsp90 inhibitors, Celasterol and Withaferin A (Zhang et al., 2008; Yu et al., 2010), reduce tau levels and a new compound, platycodin D has just been discovered (Li et al., 2017). Platycodin D does not affect the ATPase activity of Hsp90, but instead disrupts the interaction between Hsp90 and Cdc37 leading to client protein degradation without an increase in Hsp70 (Li et al., 2017). PubMed:29311797

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

The Cdc37/Hsp90 inhibitors, Celasterol and Withaferin A (Zhang et al., 2008; Yu et al., 2010), reduce tau levels and a new compound, platycodin D has just been discovered (Li et al., 2017). Platycodin D does not affect the ATPase activity of Hsp90, but instead disrupts the interaction between Hsp90 and Cdc37 leading to client protein degradation without an increase in Hsp70 (Li et al., 2017). PubMed:29311797

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a(CHEBI:tanespimycin) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Another N-terminal Hsp90 ATPase inhibitor, 17- AAG, was shown to decrease levels of phosphorylated tau in cells, and a related N-terminal Hsp90 ATPase inhibitor, PU- DZ8, reduced soluble and insoluble tau in tauP301L mice (Luo et al., 2007). PubMed:29311797

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a(PUBCHEM:14719853) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Another N-terminal Hsp90 ATPase inhibitor, 17- AAG, was shown to decrease levels of phosphorylated tau in cells, and a related N-terminal Hsp90 ATPase inhibitor, PU- DZ8, reduced soluble and insoluble tau in tauP301L mice (Luo et al., 2007). PubMed:29311797

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bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

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bp(GO:"chaperone-mediated autophagy") association p(FPLX:HSP90) View Subject | View Object

Hsp90 and Hop are both involved in the CMA system; PubMed:29311797

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bp(HBP:Proteostasis) association p(FPLX:HSP90) View Subject | View Object

Hsp90 is critical to maintaining proteostasis (Brehme et al., 2014) and accounts for up to 6% of all protein within the cell during times of stress (Picard, 2002; Prodromou, 2016). PubMed:29311797

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bp(MESH:Aging) increases p(FPLX:HSP90) View Subject | View Object

One study focused on the basal levels of cytosolic Hsp90 in peripheral blood mononuclear cells (PBMC) and found that in aged human samples there was an increase in Hsp90 under normal physiological conditions when compared to young samples (Njemini et al., 2007). PubMed:29311797

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Annotations
Cell Ontology (CL)
peripheral blood mononuclear cell

bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

Conversely, there are also studies showing decreased levels of Hsp90 in aged human brain samples. PubMed:29311797

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Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

One study found that cytosolic Hsp90 was repressed in the superior frontal gyrus, while another demonstrated a similar repression in the prefrontal cortex of aged patients compared to controls (Berchtold et al., 2008; Loerch et al., 2008; Brehme et al., 2014). PubMed:29311797

Appears in Networks:
Annotations
Uberon
prefrontal cortex
Uberon
superior frontal gyrus

complex(a(CHEBI:ATP), p(FPLX:HSP90)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:AIP)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:CDC37)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:FKBP4), p(HGNC:PTGES3), p(HGNC:STIP1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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p(HGNC:PTGES3) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

p23 has an opposing effect on Hsp90 compared to Aha1. p23 works by inhibiting the ATPase activity of Hsp90. PubMed:29311797

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complex(p(FPLX:HSP90), p(HGNC:FKBP6)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:FKBP8)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:FKBPL)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:FNIP1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:FNIP1)) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

The folliculin-interacting protein 1 (FNIP1) is able to interact with Hsp90 as a co-chaperone in order to inhibit its ATPase activity. PubMed:29311797

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complex(p(FPLX:HSP90), p(HGNC:FNIP1), p(HGNC:FNIP2)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:PPP5C)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:S100A1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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p(FPLX:HSP90, pmod(NO)) decreases act(p(FPLX:HSP90)) View Subject | View Object

S-nitrosylation, oxidation and ubiquitination also inhibit Hsp90 chaperone activity (Blank et al., 2003; Martínez-Ruiz et al., 2005; Chen et al., 2008). PubMed:29311797

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p(FPLX:HSP90, pmod(Ph)) decreases act(p(FPLX:HSP90)) View Subject | View Object

Phosphorylation of Hsp90 leads to reduced chaperoning ability and phosphorylation of specific tyrosine residues can affect the ability of Hsp90 to interact with distinct client proteins (Zhao et al., 2001; Mollapour and Neckers, 2012). PubMed:29311797

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p(FPLX:HSP90, pmod(Ub)) decreases act(p(FPLX:HSP90)) View Subject | View Object

S-nitrosylation, oxidation and ubiquitination also inhibit Hsp90 chaperone activity (Blank et al., 2003; Martínez-Ruiz et al., 2005; Chen et al., 2008). PubMed:29311797

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p(HGNC:AHSA1) increases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

The activator of Hsp90 ATPase homolog 1 (Aha1) works as a co- chaperone to stimulate the ATPase function of Hsp90 to regulate the folding and activation of client proteins. PubMed:29311797

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Annotations
MeSH
Cerebral Cortex

composite(p(FPLX:HSP90), p(HGNC:SUGT1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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bp(HBP:Proteostasis) association p(FPLX:HSP90) View Subject | View Object

Many studies based on model systems support a role for candidates from each of the major chaperome families; HSP100, HSP90, HSP70, HSP60, HSP40, sHSPs, and TPR-domain-containing proteins in proteostasis. PubMed:27491084

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a(CHEBI:ATP) regulates act(p(FPLX:HSP90)) View Subject | View Object

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein. PubMed:23746257

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bp(GO:"'de novo' protein folding") association act(p(FPLX:HSP90)) View Subject | View Object

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein. PubMed:23746257

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bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b). PubMed:23746257

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bp(GO:"calcium-mediated signaling") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(GO:"cell cycle") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(GO:"immune response") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(GO:"protein refolding") association act(p(FPLX:HSP90)) View Subject | View Object

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein. PubMed:23746257

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bp(GO:"protein secretion") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(GO:"protein transport") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(GO:"steroid hormone mediated signaling pathway") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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bp(MESH:"Heat-Shock Response") association p(FPLX:HSP90) View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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complex(a(CHEBI:ATP), p(FPLX:HSP90)) regulates act(p(FPLX:HSP90)) View Subject | View Object

Inhibition of ATP binding and hydrolysis either by mutagenesis of the N domain or by specific inhibitors, such as geldanamycin and radicicol, demonstrated the functional requirement of the Hsp90 ATPase (81, 169). PubMed:23746257

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composite(p(FPLX:HSP90), p(FPLX:HSPA), p(HGNC:BAG1), p(HGNC:BAG3), p(HGNC:STUB1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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p(HGNC:AHSA1) increases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

The activator of Hsp90 ATPase (Aha1) binds asymmetrically to the Hsp90 middle domain, stimulating ATP hydrolysis and inducing transition to the closed state (180, 181, 185, 190). PubMed:23746257

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p(HGNC:CDC37) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Cochaperones HOP (Sti1) and Cdc37 (p50) stabilize the open conformation of the Hsp90 dimer (81, 174, 175, 188), inhibit ATP hydrolysis, and facilitate substrate protein binding. PubMed:23746257

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p(HGNC:STIP1) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Cochaperones HOP (Sti1) and Cdc37 (p50) stabilize the open conformation of the Hsp90 dimer (81, 174, 175, 188), inhibit ATP hydrolysis, and facilitate substrate protein binding. PubMed:23746257

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complex(a(MESH:"HSP70 Heat-Shock Proteins"), p(FPLX:HSP90), p(HGNC:STUB1)) hasComponent p(FPLX:HSP90) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:STUB1), p(MESH:Proteins, pmod(HBP:misfolded))) hasComponent p(FPLX:HSP90) View Subject | View Object

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Out-Edges 48

p(FPLX:HSP90) regulates a(HBP:"Tau aggregates") View Subject | View Object

However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797

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

The ATP-dependent chaperones are comprised of the 5 HSP90s, 17 HSP70s, 14 HSP60s, 6 ER-specific, and 8 MITO-specific Hsp100/AAA+ ATPases, respectively. PubMed:25437566

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p(FPLX:HSP90) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

This functional screen identified 18 genes (Figure 3D), corresponding to ten ATP-dependent chaperones, HSC70 (hsp-1), HSP90 (daf-21), and eight subunits of the CCT/TRiC chaperonin complex; the co-chaperones, HSP40 (dnj-12) and CDC37 (cdc-37); and the TPR-domain pro- tein STI1 that upon knockdown significantly enhanced A b 42 pro- teotoxicity (Figure 3D). PubMed:25437566

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

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

Knockdown of daf-21 (HSP90) or hsp-1 (HSC70) led to increased paralysis in 45% and 44% of day 6 animals, respectively, and knockdown of TPR co-chaper- ones tpr-1 and dnj-12 resulted in 70% impairment (Figure S4D). PubMed:25437566

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

p(FPLX:HSP90) isA a(MESH:"Molecular Chaperones") View Subject | View Object

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p(FPLX:HSP90) regulates bp(GO:"protein folding") View Subject | View Object

As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination. PubMed:25784053

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p(FPLX:HSP90) regulates bp(MESH:Proteolysis) View Subject | View Object

As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination. PubMed:25784053

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act(p(FPLX:HSP90)) decreases act(p(HGNC:HSF1)) View Subject | View Object

One strategy is to directly activate HSF1, thereby increasing the expression of multiple molecular chaperones simultaneously. This approach has been traditionally achieved by inhibition of HSP90 with compounds that bind the N-terminal ATP-binding pocket, such as radicicol, geldanamycin, or 17-AAG (64, 132–134). PubMed:25784053

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Annotations
Cell Ontology (CL)
motor neuron

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

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]. PubMed:21882945

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

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 PubMed:21882945

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

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 PubMed:21882945

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

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 PubMed:21882945

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

Alternatively, either Hsp70 or Hsp90 can recruit the ubiquitin E3 ligase, C-terminal Hsp70 interacting protein (CHIP), to degrade the bound substrate [104] PubMed:21882945

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

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] PubMed:21882945

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

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 PubMed:21882945

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

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945

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

Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau PubMed:21882945

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

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945

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

Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau PubMed:21882945

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p(FPLX:HSP90) association bp(HBP:Proteostasis) View Subject | View Object

Hsp90 is critical to maintaining proteostasis (Brehme et al., 2014) and accounts for up to 6% of all protein within the cell during times of stress (Picard, 2002; Prodromou, 2016). PubMed:29311797

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p(FPLX:HSP90) hasVariant p(FPLX:HSP90, pmod(Ac)) View Subject | View Object

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p(FPLX:HSP90) hasVariant p(FPLX:HSP90, pmod(NO)) View Subject | View Object

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p(FPLX:HSP90) hasVariant p(FPLX:HSP90, pmod(Ph)) View Subject | View Object

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p(FPLX:HSP90) hasVariant p(FPLX:HSP90, pmod(Ub)) View Subject | View Object

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act(p(FPLX:HSP90)) increases bp(MESH:Proteolysis) View Subject | View Object

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

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act(p(FPLX:HSP90)) increases bp(GO:"protein folding") View Subject | View Object

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

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act(p(FPLX:HSP90)) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

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p(FPLX:HSP90) regulates path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797

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

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011). PubMed:29311797

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

In addition to the problems faced with an overwhelmed chaperone network, the proteolytic activity of the proteasome also declines with aging, and in fact Hsp90 has been shown to protect the proteasome from age-related, oxidative-dependent decline (Conconi and Friguet, 1997). PubMed:29311797

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p(FPLX:HSP90) association bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Hsp90 and Hop are both involved in the CMA system; PubMed:29311797

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act(p(FPLX:HSP90), ma(GO:"ATPase activity")) increases path(MESH:Tauopathies) View Subject | View Object

Inhibition of the ATPase activity of Hsp90 has been shown to have positive outcomes in cell culture and animal models of tauopathy. PubMed:29311797

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

Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice. PubMed:29311797

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

Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice. PubMed:29311797

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p(FPLX:HSP90) association bp(HBP:Proteostasis) View Subject | View Object

Many studies based on model systems support a role for candidates from each of the major chaperome families; HSP100, HSP90, HSP70, HSP60, HSP40, sHSPs, and TPR-domain-containing proteins in proteostasis. PubMed:27491084

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act(p(FPLX:HSP90)) association bp(GO:"'de novo' protein folding") View Subject | View Object

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein. PubMed:23746257

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act(p(FPLX:HSP90)) association bp(GO:"protein refolding") View Subject | View Object

Chaperones that function broadly in de novo folding and refolding (i.e., the chaperonins, Hsp70s, and Hsp90s) are ATP regulated and recognize segments of exposed hydropho- bic amino acid residues, which are later buried in the interior of the natively folded protein. PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"cell cycle") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"steroid hormone mediated signaling pathway") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"calcium-mediated signaling") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"protein transport") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"protein secretion") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(GO:"immune response") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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p(FPLX:HSP90) association bp(MESH:"Heat-Shock Response") View Subject | View Object

Accordingly, Hsp90 affects many key cellular processes, including cell cycle progression, steroid signaling, calcium signaling, protein trafficking, protein secretion, the immune re- sponse, and the heat shock response (HSR) (45, 48, 82). PubMed:23746257

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act(p(FPLX:HSP90)) increases bp(GO:"protein folding") View Subject | View Object

After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b). PubMed:23746257

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p(FPLX:HSP90) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

n general, HSP90s are more specialized than other chaperones and are essential for survival in eukaryotic cells as they also are capable of binding non-native polypeptides (at the late stages of their folding) and preventing their aggregation [14]. PubMed:24563850

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

Recent data suggest that a critical mediator of refolding or clearance of hyperphosphorylated tau is via the HSP70/HSP90 heat shock pathways in which a specific E3 ubiquitin ligase, CHIP (carboxy terminus Hsp70 interacting protein), can recognize and target for degradation abnormal but not normal tau molecules [14–16]. PubMed:25374103

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

Several publications suggest that molecular chaperones, e.g., heat shock protein 70 and 90 (Hsp70, Hsp90) play a fundamental role in the clearance of misfolded proteins including tau [12]. PubMed:25374103

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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.