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Molecular Chaperones 3.0
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Molecular Chaperones 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 21589

Special Issue Editor

Prof. Dr. Hideaki Itoh

E-Mail Website
Guest Editor
Department of Life Science, Graduate School and Faculty of Engineering and Resource Science, Akita University, Akita 010-8502, Japan
Interests: hsp60; eurodegeneration microglia innate immunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Homeostasis is essential for maintaining cell function. For that purpose, proteins must fold to their native state to achieve functionality. Many heat shock proteins (HSPs) perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by cell stress. Molecular chaperones belong to the family of conservative proteins with a high homology of the primary structure in both the prokaryote and eukaryote. HSPs are often classified according to their molecular weight and members include HSP90, HSP70, HSP60, and small HSPs. Molecular chaperones have a large functional diversity. Their fundamental roles include de novo folding and the refolding of misfolded proteins. Chaperones also regulate critical cellular processes, such as protein trafficking, protein degradation, protein complex assembly, and regulate functional proteins, such as steroid hormone receptors. The uniqueness of molecular chaperones results from their ability to interact with a very large number of different proteins called clients. HSPs provide protection from cellular and environmental stress factors as molecular chaperones to maintain protein homeostasis. This Special Issue will include original research papers and outstanding reviews that show the role of molecular chaperones in the functionality of homeostasis in the cell.

Prof. Dr. Hideaki Itoh
Guest Editor

Manuscript Submission Information

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Keywords

  • Molecular chaperone
  • Heat shock protein (HSPs)
  • HSP90, HSP70, HSP60
  • De novo folding
  • Misfolded protein
  • Protein trafficking
  • Protein degradation
  • Protein complex assembly
  • Homeostasis

Published Papers (7 papers)

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Research

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16 pages, 2802 KiB  
Article
The Archaeal Small Heat Shock Protein Hsp17.6 Protects Proteins from Oxidative Inactivation
by Pengfei Ma, Jie Li, Lei Qi and Xiuzhu Dong
Int. J. Mol. Sci. 2021, 22(5), 2591; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052591 - 04 Mar 2021
Cited by 12 | Viewed by 2081
Abstract
Small heat shock proteins (sHsps) are widely distributed among various types of organisms and function in preventing the irreversible aggregation of thermal denaturing proteins. Here, we report that Hsp17.6 from Methanolobus psychrophilus exhibited protection of proteins from oxidation inactivation. The overexpression of Hsp17.6 [...] Read more.
Small heat shock proteins (sHsps) are widely distributed among various types of organisms and function in preventing the irreversible aggregation of thermal denaturing proteins. Here, we report that Hsp17.6 from Methanolobus psychrophilus exhibited protection of proteins from oxidation inactivation. The overexpression of Hsp17.6 in Escherichia coli markedly increased the stationary phase cell density and survivability in HClO and H2O2. Treatments with 0.2 mM HClO or 10 mM H2O2 reduced malate dehydrogenase (MDH) activity to 57% and 77%, whereas the addition of Hsp17.6 recovered the activity to 70–90% and 86–100%, respectively. A similar effect for superoxide dismutase oxidation was determined for Hsp17.6. Non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis assays determined that the Hsp17.6 addition decreased H2O2-caused disulfide-linking protein contents and HClO-induced degradation of MDH; meanwhile, Hsp17.6 protein appeared to be oxidized with increased molecular weights. Mass spectrometry identified oxygen atoms introduced into the larger Hsp17.6 molecules, mainly at the aspartate and methionine residues. Substitution of some aspartate residues reduced Hsp17.6 in alleviating H2O2- and HClO-caused MDH inactivation and in enhancing the E. coli survivability in H2O2 and HClO, suggesting that the archaeal Hsp17.6 oxidation protection might depend on an “oxidant sink” effect, i.e., to consume the oxidants in environments via aspartate oxidation. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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22 pages, 16857 KiB  
Article
Mutation of GGMP Repeat Segments of Plasmodium falciparum Hsp70-1 Compromises Chaperone Function and Hop Co-Chaperone Binding
by Stanley Makumire, Tendamudzimu Harmfree Dongola, Graham Chakafana, Lufuno Tshikonwane, Cecilia Tshikani Chauke, Tarushai Maharaj, Tawanda Zininga and Addmore Shonhai
Int. J. Mol. Sci. 2021, 22(4), 2226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042226 - 23 Feb 2021
Cited by 13 | Viewed by 3170
Abstract
Parasitic organisms especially those of the Apicomplexan phylum, harbour a cytosol localised canonical Hsp70 chaperone. One of the defining features of this protein is the presence of GGMP repeat residues sandwiched between α-helical lid and C-terminal EEVD motif. The role of the GGMP [...] Read more.
Parasitic organisms especially those of the Apicomplexan phylum, harbour a cytosol localised canonical Hsp70 chaperone. One of the defining features of this protein is the presence of GGMP repeat residues sandwiched between α-helical lid and C-terminal EEVD motif. The role of the GGMP repeats of Hsp70s remains unknown. In the current study, we introduced GGMP mutations in the cytosol localised Hsp70-1 of Plasmodium falciparum (PfHsp70-1) and a chimeric protein (KPf), constituted by the ATPase domain of E. coli DnaK fused to the C-terminal substrate binding domain of PfHsp70-1. A complementation assay conducted using E. coli dnaK756 cells demonstrated that the GGMP motif was essential for chaperone function of the chimeric protein, KPf. Interestingly, insertion of GGMP motif of PfHsp70-1 into DnaK led to a lethal phenotype in E. coli dnaK756 cells exposed to elevated growth temperature. Using biochemical and biophysical assays, we established that the GGMP motif accounts for the elevated basal ATPase activity of PfHsp70-1. Furthermore, we demonstrated that this motif is important for interaction of the chaperone with peptide substrate and a co-chaperone, PfHop. Our findings suggest that the GGMP may account for both the specialised chaperone function and reportedly high catalytic efficiency of PfHsp70-1. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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13 pages, 1967 KiB  
Article
Various Anti-HSPA2 Antibodies Yield Different Results in Studies on Cancer-Related Functions of Heat Shock Protein A2
by Dorota Scieglinska, Damian Robert Sojka, Agnieszka Gogler-Pigłowska, Vira Chumak and Zdzisław Krawczyk
Int. J. Mol. Sci. 2020, 21(12), 4296; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124296 - 16 Jun 2020
Cited by 5 | Viewed by 3050
Abstract
Heat shock proteins (HSPs) constitute a major part of the molecular chaperone system and play a fundamental role in cell proteostasis. The HSPA (HSP70) family groups twelve highly homologous HSPA proteins. Certain HSPAs are regarded as important cancer-related proteins, prospective therapeutic targets for [...] Read more.
Heat shock proteins (HSPs) constitute a major part of the molecular chaperone system and play a fundamental role in cell proteostasis. The HSPA (HSP70) family groups twelve highly homologous HSPA proteins. Certain HSPAs are regarded as important cancer-related proteins, prospective therapeutic targets for cancer treatment, and also as potential cancer biomarkers. Heat Shock Protein A2 (HSPA2), a testis-enriched chaperone and one of the least characterized members of the HSPA family, has recently emerged as an important cancer-relevant protein with potential biomarker significance. Nevertheless, conflicting conclusions have been recently drawn both according to HSPA2 role in cancer cells, as well as to its prognostic value. In this work we have shown that one of the serious limitations in HSPA2 protein research is cross-reactivity of antibodies marketed as specific for HSPA2 with one or more other HSPA(s). Among non-specific antibodies were also those recently used for HSPA2 detection in functional and biomarker studies. We showed how using non-specific antibodies can generate misleading conclusions on HSPA2 expression in non-stressed cancer cells and tumors, as well as in cancer cells exposed to proteotoxic stress. Our findings addressed concerns on some published studies dealing with HSPA2 as a cancer-related protein. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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26 pages, 8048 KiB  
Article
Identification of Substrates of Cytoplasmic Peptidyl-Prolyl Cis/Trans Isomerases and Their Collective Essentiality in Escherichia Coli
by Gracjana Klein, Pawel Wojtkiewicz, Daria Biernacka, Anna Stupak, Patrycja Gorzelak and Satish Raina
Int. J. Mol. Sci. 2020, 21(12), 4212; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124212 - 13 Jun 2020
Cited by 7 | Viewed by 3049
Abstract
Protein folding often requires molecular chaperones and folding catalysts, such as peptidyl-prolyl cis/trans isomerases (PPIs). The Escherichia coli cytoplasm contains six well-known PPIs, although a requirement of their PPIase activity, the identity of their substrates and relative enzymatic contribution is unknown. Thus, strains [...] Read more.
Protein folding often requires molecular chaperones and folding catalysts, such as peptidyl-prolyl cis/trans isomerases (PPIs). The Escherichia coli cytoplasm contains six well-known PPIs, although a requirement of their PPIase activity, the identity of their substrates and relative enzymatic contribution is unknown. Thus, strains lacking all periplasmic and one of the cytoplasmic PPIs were constructed. Measurement of their PPIase activity revealed that PpiB is the major source of PPIase activity in the cytoplasm. Furthermore, viable Δ6ppi strains could be constructed only on minimal medium in the temperature range of 30–37 °C, but not on rich medium. To address the molecular basis of essentiality of PPIs, proteins that aggregate in their absence were identified. Next, wild-type and putative active site variants of FkpB, FklB, PpiB and PpiC were purified and in pull-down experiments substrates specific to each of these PPIs identified, revealing an overlap of some substrates. Substrates of PpiC were validated by immunoprecipitations using extracts from wild-type and PpiC-H81A strains carrying a 3xFLAG-tag appended to the C-terminal end of the ppiC gene on the chromosome. Using isothermal titration calorimetry, RpoE, RseA, S2, and AhpC were established as FkpB substrates and PpiC’s PPIase activity was shown to be required for interaction with AhpC. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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Review

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12 pages, 1157 KiB  
Review
Molecular Chaperones and Thyroid Cancer
by Letizia Paladino, Alessandra Maria Vitale, Radha Santonocito, Alessandro Pitruzzella, Calogero Cipolla, Giuseppa Graceffa, Fabio Bucchieri, Everly Conway de Macario, Alberto J. L. Macario and Francesca Rappa
Int. J. Mol. Sci. 2021, 22(8), 4196; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084196 - 18 Apr 2021
Cited by 8 | Viewed by 2482
Abstract
Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of [...] Read more.
Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of the chaperone system (CS). Components of the CS are found to be quantitatively increased or decreased, and some correlations have been established between the quantitative changes and tumor type, prognosis, and response to treatment. These correlations provide the basis for identifying distinctive patterns useful in differential diagnosis and for planning experiments aiming at elucidating the role of the CS in tumorigenesis. Here, we discuss studies of the CS components in various thyroid cancers (TC). The chaperones belonging to the families of the small heat-shock proteins Hsp70 and Hsp90 and the chaperonin of Group I, Hsp60, have been quantified mostly by immunohistochemistry and Western blot in tumor and normal control tissues and in extracellular vesicles. Distinctive differences were revealed between the various thyroid tumor types. The most frequent finding was an increase in the chaperones, which can be attributed to the augmented need for chaperones the tumor cells have because of their accelerated metabolism, growth, and division rate. Thus, chaperones help the tumor cell rather than protect the patient, exemplifying chaperonopathies by mistake or collaborationism. This highlights the need for research on chaperonotherapy, namely the development of means to eliminate/inhibit pathogenic chaperones. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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23 pages, 2575 KiB  
Review
Role of the HSP70 Co-Chaperone SIL1 in Health and Disease
by Viraj P. Ichhaporia and Linda M. Hendershot
Int. J. Mol. Sci. 2021, 22(4), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041564 - 04 Feb 2021
Cited by 10 | Viewed by 3529
Abstract
Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes [...] Read more.
Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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12 pages, 20936 KiB  
Review
Cardioprotective Role of Heat Shock Proteins in Atrial Fibrillation: From Mechanism of Action to Therapeutic and Diagnostic Target
by Stan W. van Wijk, Kennedy S. Ramos and Bianca J. J. M. Brundel
Int. J. Mol. Sci. 2021, 22(1), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010442 - 05 Jan 2021
Cited by 10 | Viewed by 3268
Abstract
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) [...] Read more.
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment. Full article
(This article belongs to the Special Issue Molecular Chaperones 3.0)
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