Pathways of allosteric regulation in Hsp70 chaperones

Kityk, Roman; Vogel, Markus; Schlecht, Rainer; Bukau, Bernd; Mayer, Mathias

doi:10.1038/ncomms9308

Cited by 116 publications

(248 citation statements)

References 60 publications

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“…GrpE enhances the release of ADP by DnaK so that ATP can bind to restart the cycle. DnaK exhibits an "open" conformation when bound to ATP and shows high on/off rates for substrate, whereas it exhibits slow on/off rates and a closed conformation when bound to ADP (27)(28)(29)(30).…”

Section: Significancementioning

confidence: 99%

Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

Lupoli

Fay

Adura

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During host infection, Mycobacterium tuberculosis (Mtb) encounters several types of stress that impair protein integrity, including reactive oxygen and nitrogen species and chemotherapy. The resulting protein aggregates can be resolved or degraded by molecular machinery conserved from bacteria to eukaryotes. Eukaryotic Hsp104/Hsp70 and their bacterial homologs ClpB/DnaK are ATP-powered chaperones that restore toxic protein aggregates to a native folded state. DnaK is essential in Mycobacterium smegmatis, and ClpB is involved in asymmetrically distributing damaged proteins during cell division as a mechanism of survival in Mtb, commending both proteins as potential drug targets. However, their molecular partners in protein reactivation have not been characterized in mycobacteria. Here, we reconstituted the activities of the Mtb ClpB/DnaK bichaperone system with the cofactors DnaJ1, DnaJ2, and GrpE and the small heat shock protein Hsp20. We found that DnaJ1 and DnaJ2 activate the ATPase activity of DnaK differently. A point mutation in the highly conserved HPD motif of the DnaJ proteins abrogates their ability to activate DnaK, although the DnaJ2 mutant still binds to DnaK. The purified Mtb ClpB/DnaK system reactivated a heat-denatured model substrate, but the DnaJ HPD mutants inhibited the reaction. Finally, either DnaJ1 or DnaJ2 is required for mycobacterial viability, as is the DnaK-activating activity of a DnaJ protein. These studies lay the groundwork for strategies to target essential chaperone–protein interactions in Mtb, the leading cause of death from a bacterial infection.

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Section: Significancementioning

confidence: 99%

Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

Lupoli

Fay

Adura

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In order to participate in a series of physiological functions, a (large) HSP has to be detached from its client peptides (proteins). HSP70 and other chaperones utilize an ATPase domain to hydrolyze ATP and then take on a free conformation [163]. The small HSP27 does not have such an ATPase domain, and HSP70 can react to take away the clients from HSP27; therefore, HSP70 appears to play role in "activating" the smaller HSPs.…”

Section: Overexpression Of Constitutive Hsps Is Not the Cause But Thmentioning

confidence: 99%

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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Heat shock proteins (HSPs) serve to correct proteins' conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis-a "passive approach". On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells; on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the "active approach". On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain "mysteries" behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

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“…The first type includes Hsp27, Hsp70 and Hsp90, and they interact directly with the surfaces of unfolded proteins[4–6] (Box1). By contrast, the second type (which includes the chaperonin Hsp60) assembles into complexes resembling folding chambers, which form privileged environments that exclude bulk cytoplasm and favor recovery of active protein conformations[7].…”

Section: Introduction To Hsps Chaperones and Cancermentioning

confidence: 99%

Heat Shock Proteins Promote Cancer: It's a Protection Racket

Calderwood

Gong

2016

Trends in Biochemical Sciences

334

251

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Heat Shock Proteins (HSP) are expressed at high levels in cancer and form a fostering environment essential for tumor development. We have reviewed the recent data in this area, concentrating mainly on Hsp27, Hsp70 and Hsp90. The overriding role of the HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer gene. Elevated HSPs are thus required for many of the traits that underlie the morbidity of cancer, including increased growth, survival and formation of secondary cancers. In addition, HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor- mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.

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Pathways of allosteric regulation in Hsp70 chaperones

Cited by 116 publications

References 60 publications

Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Heat Shock Proteins Promote Cancer: It's a Protection Racket

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