p(INTERPRO:"Heat shock protein 70 family")

Entity

Name

Heat shock protein 70 family

Namespace

interpro

Namespace Version

20181021

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/f2f993e599694ab5ce989cc39d789a499f75db99/external/interpro-names.belns

BAG proteins comprise a family of homologous cochaperones for Hsp70. All of these proteins regulate Hsp70’s ATPase activity, interacting with Hsp70 through a conserved BAG domain in their C termini (Figure 3D; Kampinga and Craig, 2010) PubMed:25036637

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 PubMed:21882945

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 PubMed:21882945

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 PubMed:21882945

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). PubMed:21882945

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 PubMed:21882945

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 PubMed:21882945

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). PubMed:21882945

The location of the hsc70-binding site in the tau MTBR suggests that hsc70 cannot bind microtubule-associated tau. The location of the hsc70-binding site also suggests that hsc70 might compete with tubulin or microtubules for binding to tau. Our data implicating I308/V309 in tau’s binding to hsp70 similarly suggest that tau cannot bind simultaneously to hsp70 and microtubules. However, unlike hsc70, which does not associate directly with tubulin or microtubules (Gache et al. 2005), hsp70 binds microtubules, presumably through its N-terminus (Sanchez et al. 1994). This would allow hsp70 to simultaneously bind to tau through its C-terminal substrate-binding domain and to microtubules through its N-terminus. PubMed:18500754

For example, Hsp70 and Hsp90 machineries formed distinct clusters: Hsp70 clustered together with Hsc70, their nucleotide-exchange factor BAG2, and the E3 ligase CHIP (Figure 5A, orange cluster), whereas Hsp90 and many of its cochaperones formed a separate group (Figure 5A, blue cluster) PubMed:25036637

Hsp90beta interacted particularly strongly with kinases (Figure 5B, filled blue circles), whereas the transcription factors p53 and HSF1 were among the most Hsp70-biased interactors (Figure 5B,green circles) PubMed:25036637

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

Hsp70 has been shown to both stabilize binding of tau to microtubules [114] and promote its degradation in combination with CHIP [115,116] PubMed:21882945

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] PubMed:21882945

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] PubMed:21882945

The location of the hsc70-binding site in the tau MTBR suggests that hsc70 cannot bind microtubule-associated tau. The location of the hsc70-binding site also suggests that hsc70 might compete with tubulin or microtubules for binding to tau. Our data implicating I308/V309 in tau’s binding to hsp70 similarly suggest that tau cannot bind simultaneously to hsp70 and microtubules. However, unlike hsc70, which does not associate directly with tubulin or microtubules (Gache et al. 2005), hsp70 binds microtubules, presumably through its N-terminus (Sanchez et al. 1994). This would allow hsp70 to simultaneously bind to tau through its C-terminal substrate-binding domain and to microtubules through its N-terminus. PubMed:18500754