Molecular Chaperone HSP70 and Key Regulators of Apoptosis - A Review

Identified as a molecular chaperone constitutively being synthesized due to enhanced elevated temperature change, this heat shock protein HSP70 has shown to be intimately involved in many protein biogenesis, facilitating the synthesis and folding of proteins and trafficking of nascent peptides during cell growth. HSP70 also plays a vital role in protein assembly, regulation and interaction with a wide variety of proteins. Stress-induced cell death is under the control of the Bcl-2 family of apoptotic regulators and display either pro-apoptotic or anti-apoptotic activities. Subjected to stress conditions such as heat shock, cells have been reported to express elevated expressions of HSP70. Moreover, this molecular chaperon has shown to act at multiple levels to suppress stressed-induced apoptotic signals of some Bcl-2 members by repairing, re-synthesizing damaged proteins, and stabilizing unfolded proteins. Therefore, HSP70 synthesis can act as an essential recovery mode for cellular survival and adaptation during lethal conditions.

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HSP70 and lysosomal storage disorders: novel therapeutic opportunities

Biochemical Society Transactions ◽

10.1042/bst0381479 ◽

2010 ◽

Vol 38 (6) ◽

pp. 1479-1483 ◽

Cited By ~ 17

Author(s):

Nikolaj H.T. Petersen ◽

Thomas Kirkegaard

Keyword(s):

Heat Shock ◽

Stress Responses ◽

Molecular Chaperone ◽

Heat Shock Protein 70 ◽

Physiological Stress ◽

Lysosomal Storage ◽

Catabolic Enzymes ◽

Chaperone Hsp70 ◽

Storage Disorders ◽

Novel Therapeutic

Lysosomes, with their arsenal of catabolic enzymes and crucial metabolic housekeeping functions are experiencing a revived research interest after having lived a rather quiet life for the last few decades. With the discovery of the interaction of the lysosomes with another ancient component of cellular homoeostasis, the molecular chaperone HSP70 (heat-shock protein 70), the stage seems set for further discoveries of the mechanisms regulating cellular and physiological stress responses to otherwise detrimental challenges.

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Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

eLife ◽

10.7554/elife.18638 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 86

Author(s):

Xu Zheng ◽

Joanna Krakowiak ◽

Nikit Patel ◽

Ali Beyzavi ◽

Jideofor Ezike ◽

...

Keyword(s):

Mathematical Model ◽

Heat Shock ◽

Signaling Pathways ◽

Molecular Chaperones ◽

Stress Resistance ◽

Dynamic Control ◽

Protein Homeostasis ◽

Unfolded Proteins ◽

Cell Signaling Pathways ◽

Chaperone Hsp70

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

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Characterization of the Relationship between the Chaperone and Lipid-Binding Functions of the 70-Kda Heat-Shock Protein, HspA1A

10.20944/preprints202005.0150.v1 ◽

2020 ◽

Author(s):

Larissa Smulders ◽

Amanda Daniels ◽

Caroline Plescia ◽

Devon Burger ◽

Robert V. Stahelin ◽

...

Keyword(s):

Radiation Therapy ◽

Plasma Membrane ◽

Heat Shock ◽

Secondary Structure ◽

Molecular Chaperone ◽

Inorganic Phosphate ◽

Lipid Binding ◽

Cellular Survival ◽

The Relationship

HspA1A is a molecular chaperone that plays indispensable roles in cellular survival. HspA1A also translocates to the plasma membrane (PM) of stressed and cancer cells. This translocation results in the cell-surface presentation of HspA1A rendering these tumors radiation insensitive. Thus, a putative therapeutic would be to inhibit HspA1A’s PM translocation. However, to specifically stop the PM translocation of HspA1A, which is lipid-driven, it is imperative to characterize the lipid-binding regions of HspA1A and the relationship between the chaperone and lipid-binding functions of HspA1A, which remain unknown. To elucidate this relationship, we determined the effect of binding to phosphatidylserine (PS) on the secondary structure and chaperone functions of HspA1A. Circular dichroism revealed that binding to PS had minimal alterations on HspA1A’s secondary structure. Measuring the release of inorganic phosphate revealed that PS-binding had no effect on the ATPase activity of HspA1A. In contrast, PS-binding showed subtle but consistent increases in the refolding activities of HspA1A. These observations strongly support the notion that the chaperone and lipid-binding activities of HspA1A are dependent but the regions mediating these functions do not overlap. These findings provide the basis for future interventions to inhibit HspA1A’s PM-translocation in tumor cells, making them sensitive to radiation therapy.

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Unique unfoldase/aggregase activity of a molecular chaperone that dysregulates a translational elongation factor

10.1101/492876 ◽

2018 ◽

Author(s):

Ku-Sung Jo ◽

Ji-Hun Kim ◽

Kyoung-Seok Ryu ◽

Young-Ho Lee ◽

Che-Yeon Wang ◽

...

Keyword(s):

Heat Shock ◽

Molecular Chaperone ◽

Elongation Factor ◽

Reduced Form ◽

Nucleotide Binding Domain ◽

Cellular Survival ◽

Redox Switch ◽

Guanine Nucleotide Binding ◽

Shock Proteins

The various chaperone activities of heat shock proteins contribute to ensuring cellular proteostasis. Here, we demonstrate the non-canonical unfoldase activity as an inherent functionality of the prokaryotic molecular chaperone Hsp33. The holding-inactive, reduced form of Hsp33 (RHsp33) strongly bound to the translational elongation factor, EF-Tu, and catalyzed the EF-Tu aggregation via evoking its aberrant folding, resulting in its susceptibility to proteolytic degradation by Lon. This interaction was critically mediated by the redox-switch domain of RHsp33 and the guanine nucleotide-binding domain of EF-Tu. The RHsp33-induced in vivo aggregation of EF-Tu upon heat shock was evident in a Lon-deficient strain and inhibited cell growth. Unlike wild-type Escherichia coli, the strain lacking both Hsp33 and Lon showed a non-reduced level of EF-Tu and diminished capability of counteracting heat shock. These findings suggest that the unique unfoldase/aggregase activity of Hsp33 potentially involved in protein turnover confers a cellular survival advantage under heat-stressed conditions.

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Heat shock protein 90 inhibition: rationale and clinical potential

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834012445574 ◽

2012 ◽

Vol 4 (4) ◽

pp. 211-218 ◽

Cited By ~ 34

Author(s):

Robert B. Den ◽

Bo Lu

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Molecular Chaperone ◽

Three Dimensional ◽

Heat Shock Protein 90 ◽

Hsp90 Inhibition ◽

Cellular Survival ◽

Chaperone Protein ◽

Cellular Stresses ◽

Clinical Potential

Heat shock protein 90 (HSP90) is a molecular chaperone protein essential for cellular survival. Functionally, HSPs promote proper protein folding, prevent misfolding, and restore three-dimensional protein structure which is critical following toxic cellular stresses. Recently, targeting HSP90 pharmacologically has gained traction in cancer therapy. Oncogenic cells depend on their ability to withstand endogenous (anoxia, nutrient deprivation, pH changes, and deranged signaling pathways) and exogenous (chemotherapy and radiation therapy) stressors for survival. Pharmacological inhibition of HSP90 destabilizes proteins and leads to degradation through the proteasome. This article will review the utility of HSP90 inhibition, as well as the current adoption in clinical trials and practice.

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Study of an influence of the intersubunit disulphide bond on the structural properties of a molecular chaperone, murine small heat shock protein HSP25

Immunology Letters ◽

10.1016/s0165-2478(97)88374-5 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 380

Author(s):

A Zavialov

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Structural Properties ◽

Molecular Chaperone ◽

Small Heat Shock Protein ◽

Disulphide Bond

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Faculty Opinions recommendation of Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1082926.535884 ◽

2007 ◽

Author(s):

Homer Pearce

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Molecular Chaperone ◽

Heat Shock Protein 90

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The Effect of Oxidized Dopamine on the Structure and Molecular Chaperone Function of the Small Heat-Shock Proteins, αB-Crystallin and Hsp27

International Journal of Molecular Sciences ◽

10.3390/ijms22073700 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3700

Author(s):

Junna Hayashi ◽

Jennifer Ton ◽

Sparsh Negi ◽

Daniel E. K. M. Stephens ◽

Dean L. Pountney ◽

...

Keyword(s):

Heat Shock ◽

Protein Aggregation ◽

Molecular Chaperone ◽

Cross Linking ◽

Αb Crystallin ◽

The Cross ◽

Shock Proteins ◽

And Function

Oxidation of the neurotransmitter, dopamine (DA), is a pathological hallmark of Parkinson’s disease (PD). Oxidized DA forms adducts with proteins which can alter their functionality. αB-crystallin and Hsp27 are intracellular, small heat-shock molecular chaperone proteins (sHsps) which form the first line of defense to prevent protein aggregation under conditions of cellular stress. In vitro, the effects of oxidized DA on the structure and function of αB-crystallin and Hsp27 were investigated. Oxidized DA promoted the cross-linking of αB-crystallin and Hsp27 to form well-defined dimer, trimer, tetramer, etc., species, as monitored by SDS-PAGE. Lysine residues were involved in the cross-links. The secondary structure of the sHsps was not altered significantly upon cross-linking with oxidized DA but their oligomeric size was increased. When modified with a molar equivalent of DA, sHsp chaperone functionality was largely retained in preventing both amorphous and amyloid fibrillar aggregation, including fibril formation of mutant (A53T) α-synuclein, a protein whose aggregation is associated with autosomal PD. In the main, higher levels of sHsp modification with DA led to a reduction in chaperone effectiveness. In vivo, DA is sequestered into acidic vesicles to prevent its oxidation and, intracellularly, oxidation is minimized by mM levels of the antioxidant, glutathione. In vitro, acidic pH and glutathione prevented the formation of oxidized DA-induced cross-linking of the sHsps. Oxidized DA-modified αB-crystallin and Hsp27 were not cytotoxic. In a cellular context, retention of significant chaperone functionality by mildly oxidized DA-modified sHsps would contribute to proteostasis by preventing protein aggregation (particularly of α-synuclein) that is associated with PD.

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