p(FPLX:HSP90)
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
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
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
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
ATP hydrolysisis essential for the chaperone activity of HSP70 and HSP90, causing conformational changes that result in substrate binding (11). PubMed:25784053
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
Among compounds that inhibit HSP90, geldanamycin promoted elimination of both hyper- phosphorylated tau and oligomeric α-synuclein in cell lines 219,220 . PubMed:30116051
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
Another HSP90 inhibitor, HSP990, has shown promise in lowering Htt aggregates and improving motor performance in two mouse models of HD 225 . PubMed:30116051
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Hsp90 and Hop are both involved in the CMA system; PubMed:29311797
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
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
Conversely, there are also studies showing decreased levels of Hsp90 in aged human brain samples. PubMed:29311797
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
p23 has an opposing effect on Hsp90 compared to Aha1. p23 works by inhibiting the ATPase activity of Hsp90. PubMed:29311797
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
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
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
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
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
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
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
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
After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b). PubMed:23746257
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
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
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
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
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
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
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
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
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
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
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
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
However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797
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
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
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
As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination. PubMed:25784053
As such, HSP70 and HSP90 are central to the process of triaging proteins for refolding or elimination. PubMed:25784053
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
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
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
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
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
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
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
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
For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945
Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau PubMed:21882945
For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945
Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau PubMed:21882945
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
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
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
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
However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797
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
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
Hsp90 and Hop are both involved in the CMA system; PubMed:29311797
Inhibition of the ATPase activity of Hsp90 has been shown to have positive outcomes in cell culture and animal models of tauopathy. PubMed:29311797
Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice. PubMed:29311797
Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice. PubMed:29311797
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
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
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
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
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
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
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
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
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
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
After hydrolysis the Hsp90 N termini separate, releasing the client protein in an active state (Figure 7b). PubMed:23746257
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
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
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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