HSPA8/HSC70 chaperone protein

Stricher, François; Macri, Christophe; Ruff, Marc; Muller, Sylviane

doi:10.4161/auto.26448

Cited by 299 publications

(153 citation statements)

References 246 publications

(239 reference statements)

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“…In normal cells, HSP90α and HSP90β reside mainly in the cytosol with minor localization in the nucleus, whereas GRP94 is found in the endoplasmic reticulum (ER) and TRAP1 in the mitochondria. Another widely expressed HSP family is the HSP70s [36–38]. The human HSP70 family contains at least eight homologous chaperone proteins.…”

Section: The Major Chaperome Membersmentioning

confidence: 99%

Selective targeting of the stress chaperome as a therapeutic strategy

Taldone

Ochiana

Patel

et al. 2014

Trends in Pharmacological Sciences

104

137

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Normal cellular function is maintained by coordinated proteome machinery that performs a vast array of activities. Helping the proteome in such roles is the chaperome, a network of molecular chaperones and folding enzymes. The stressed cell contains, at any time, a complex mixture of chaperome complexes; a majority performs “housekeeping functions” similarly to non-stressed, normal cells, but a finely-tuned fraction buffers the proteome altered by chronic stress. The stress chaperome is epigenetically distinct from its normal, housekeeping counterpart, providing a basis for its selective targeting by small molecules. Here we discuss development of chaperome inhibitors, and how agents targeting chaperome members in stressed cells are in fact being directed towards chaperome complexes and their effect is therefore determined by their ability to sample and engage such complexes. A new approach is needed to target and implement chaperome modulators in the investigation of diseases, and we propose that the classical thinking in drug discovery needs adjustment when developing chaperome-targeting drugs.

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Section: The Major Chaperome Membersmentioning

confidence: 99%

Selective targeting of the stress chaperome as a therapeutic strategy

Taldone

Ochiana

Patel

et al. 2014

Trends in Pharmacological Sciences

104

137

View full text Add to dashboard Cite

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“…They were first identified more than thirty years ago in Drosophila as 70 kD proteins that were induced by heat stress or other potentially lethal stimuli [1], [2], and found to be critical for maintaining cell survival [3], [4]. Subsequently, other HSP70 family proteins were identified in both prokaryotes and eukaryotes, with many members also shown to be constitutively expressed and exhibit important housekeeping functions [5]–[8]. Among the many activities of HSP70 family proteins are the chaperoning of nascent polypeptides and unfolding of misfolded protein substrates, the facilitation of protein transport to organelles, the protection and/or dissolution of multi-protein complexes, and the targeting of some misfolded proteins for degradation [5], [6], [9]–[12].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of the Stress-Inducible Human Heat Shock Protein 70 Substrate-Binding Domain in Complex with Peptide Substrate

et al. 2014

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The HSP70 family of molecular chaperones function to maintain protein quality control and homeostasis. The major stress-induced form, HSP70 (also called HSP72 or HSPA1A) is considered an important anti-cancer drug target because it is constitutively overexpressed in a number of human cancers and promotes cancer cell survival. All HSP70 family members contain two functional domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal protein substrate-binding domain (SBD); the latter is subdivided into SBDα and SBDβ subdomains. The NBD and SBD structures of the bacterial ortholog, DnaK, have been characterized, but only the isolated NBD and SBDα segments of eukaryotic HSP70 proteins have been determined. Here we report the crystal structure of the substrate-bound human HSP70-SBD to 2 angstrom resolution. The overall fold of this SBD is similar to the corresponding domain in the substrate-bound DnaK structures, confirming a similar overall architecture of the orthologous bacterial and human HSP70 proteins. However, conformational differences are observed in the peptide-HSP70-SBD complex, particularly in the loop Lα, β that bridges SBDα to SBDβ, and the loop LL,1 that connects the SBD and NBD. The interaction between the SBDα and SBDβ subdomains and the mode of substrate recognition is also different between DnaK and HSP70. This suggests that differences may exist in how different HSP70 proteins recognize their respective substrates. The high-resolution structure of the substrate-bound-HSP70-SBD complex provides a molecular platform for the rational design of small molecule compounds that preferentially target this C-terminal domain, in order to modulate human HSP70 function.

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“…It contains an N-terminal nucleotide binding domain and a C-terminal substrate binding domain, and interacts with Hsp40 family cochaperones and nucleotide exchange factors to accomplish protein refolding and ATP hydrolysis (32). However, ATP-independent activity has also been reported in Hsp70-family chaperones (33)(34)(35).…”

mentioning

confidence: 99%

HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

Baughman

Clouser

Klevit

et al. 2018

Journal of Biological Chemistry

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The microtubule-associated protein tau forms insoluble, amyloid-type aggregates in various dementias, most notably Alzheimer's disease. Cellular chaperone proteins play important roles in maintaining protein solubility and preventing aggregation in the crowded cellular environment. While tau is known to interact with numerous chaperones, it remains unclear how these chaperones function mechanistically to prevent tau aggregation and how chaperones from different classes compare in terms of mechanism. Here, we focused on the small heat shock protein HspB1 and the constitutive chaperone Hsc70 (also known as HspA8), and report how each chaperone interacts with tau to prevent its fibril formation. Using fluorescence and NMR spectroscopy, we show that the two chaperones inhibit tau fibril formation by distinct mechanisms. HspB1 delayed tau fibril formation by weakly interacting with early species in the aggregation process, while Hsc70 was highly efficient at preventing tau fibril elongation possibly by capping the ends of tau fibrils. Both chaperones recognized aggregation-prone motifs within the microtubule-binding repeat region of tau. However, HspB1 binding remained transient in both aggregation-promoting and nonaggregating conditions, whereas Hsc70 binding was significantly tighter under aggregationpromoting conditions. These differences highlight the fact that chaperones from different families play distinct but complementary roles in the prevention of pathological protein aggregation.

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HSPA8/HSC70 chaperone protein

Cited by 299 publications

References 246 publications

Selective targeting of the stress chaperome as a therapeutic strategy

Selective targeting of the stress chaperome as a therapeutic strategy

Crystal Structure of the Stress-Inducible Human Heat Shock Protein 70 Substrate-Binding Domain in Complex with Peptide Substrate

HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

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