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The Journal of Biological Chemistry Aug 2020Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may... (Review)
Review
Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, -GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the "chaperone code."
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Processing, Post-Translational; Structure-Activity Relationship
PubMed: 32527727
DOI: 10.1074/jbc.REV120.011833 -
Haematologica Jun 2021Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates.... (Review)
Review
Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70.
Topics: Animals; Erythroblasts; Erythrocytes; Erythropoiesis; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones
PubMed: 33832207
DOI: 10.3324/haematol.2019.233056 -
International Journal of Molecular... Oct 2019Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress... (Review)
Review
Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.
Topics: Antineoplastic Agents; Drug Therapy, Combination; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Isoxazoles; Molecular Chaperones; Neoplasms; Oligonucleotides; Resorcinols
PubMed: 31652993
DOI: 10.3390/ijms20215284 -
Non-cell Autonomous Maintenance of Proteostasis by Molecular Chaperones and Its Molecular Mechanism.Biological & Pharmaceutical Bulletin 2018Molecular chaperones have essential roles in cell survival, to prevent misfolding, aggregation, and aberrant accumulation of cellular proteins, and thus to maintain... (Review)
Review
Molecular chaperones have essential roles in cell survival, to prevent misfolding, aggregation, and aberrant accumulation of cellular proteins, and thus to maintain protein homeostasis (proteostasis). However, recent studies using animal models suggest that transcriptional upregulation of molecular chaperones in response to various types of stresses does not ubiquitously occur in all cells and tissues, but is a cell type-specific event. The imbalanced response to stresses between cells and tissues has been pointed out since more than 30 years ago, but the molecular basis as to how organisms maintain proteostasis in all cells, especially cells deficient for chaperone induction, remains unknown. In this review, I introduce the non-cell autonomous function of molecular chaperones that has been suggested in animal studies, especially focusing on our recent findings, and discuss the possibility that the non-cell autonomous function might provide a potential explanation as to how organisms would maintain proteostasis despite the imbalanced stress response between cells and tissues. Further elucidation of the molecular basis underlying the non-cell autonomous function of molecular chaperones would provide not only better understanding as to how organisms maintain proteostasis but also important insights into the potential development of therapies and diagnostics for the currently intractable neurodegenerative diseases that are associated with protein misfolding and aggregation.
Topics: Animals; Exosomes; Heat-Shock Proteins; Humans; Molecular Chaperones; Proteostasis
PubMed: 29863073
DOI: 10.1248/bpb.b18-00141 -
Neurotherapeutics : the Journal of the... Jul 2013A common pathological hallmark of protein-conformational brain diseases is the formation of disease-specific protein aggregates. In Alzheimer's disease, these are... (Review)
Review
A common pathological hallmark of protein-conformational brain diseases is the formation of disease-specific protein aggregates. In Alzheimer's disease, these are comprised of amyloid-β and Tau as opposed to α-synuclein in Parkinson's disease and N-terminal fragments of mutant huntingtin in Huntington's disease. Most aggregates also sequester molecular chaperones, a protein family that assists in the folding, refolding, stabilization, and processing of client proteins, including misfolded proteins in brain diseases. Molecular chaperone modulation has achieved remarkable therapeutic effects in some cellular and preclinical animal models of protein-conformational diseases. This has raised hope for chaperone-based strategies to combat these diseases. Here, we review briefly the functional diversity and medical significance of molecular chaperones, their therapeutic potential, and common and specific challenges towards clinical application.
Topics: Animals; Brain; Humans; Molecular Chaperones; Proteostasis Deficiencies
PubMed: 23536253
DOI: 10.1007/s13311-013-0186-5 -
Biochimica Et Biophysica Acta Aug 2014Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as... (Review)
Review
Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as cytosolic, integral membrane or exported proteins. Extensive genetic and biochemical analyses have significantly expanded our knowledge of chaperone tasking throughout this process. In bacteria, it is known that the folding of newly-synthesized cytosolic proteins is mainly orchestrated by three highly conserved molecular chaperones, namely Trigger Factor (TF), DnaK (HSP70) and GroEL (HSP60). Yet, it has been reported that these major chaperones are strongly involved in protein translocation pathways as well. This review describes such essential molecular chaperone functions, with emphasis on both the biogenesis of inner membrane proteins and the post-translational targeting of presecretory proteins to the Sec and the twin-arginine translocation (Tat) pathways. Critical interplay between TF, DnaK, GroEL and other molecular chaperones and targeting factors, including SecB, SecA, the signal recognition particle (SRP) and the redox enzyme maturation proteins (REMPs) is also discussed. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Bacteria; Cell Membrane; Chaperonin 60; HSP70 Heat-Shock Proteins; Molecular Chaperones; Oxidation-Reduction; Protein Transport; Signal Recognition Particle
PubMed: 24269840
DOI: 10.1016/j.bbamcr.2013.11.007 -
International Journal of Molecular... Feb 2024Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is... (Review)
Review
Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in , the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.
Topics: Humans; Desmin; Cardiomyopathies; Mutation; Cardiomyopathy, Restrictive; Molecular Chaperones
PubMed: 38474073
DOI: 10.3390/ijms25052826 -
Biochemistry. Biokhimiia Mar 2022* The article is published as a part of the Special Issue "Protein Misfolding and Aggregation in Cataract Disorders" (Vol. 87, No. 2). ** To whom correspondence should... (Review)
Review
* The article is published as a part of the Special Issue "Protein Misfolding and Aggregation in Cataract Disorders" (Vol. 87, No. 2). ** To whom correspondence should be addressed. Cataract is a major cause of blindness. Due to the lack of protein turnover, lens proteins accumulate age-related and environmental modifications that alter their native conformation, leading to the formation of aggregation-prone intermediates, as well as insoluble and light-scattering aggregates, thus compromising lens transparency. The lens protein, α-crystallin, is a molecular chaperone that prevents protein aggregation, thereby maintaining lens transparency. However, mutations or post-translational modifications, such as oxidation, deamidation, truncation and crosslinking, can render α-crystallins ineffective and lead to the disease exacerbation. Here, we describe such mutations and alterations, as well as their consequences. Age-related modifications in α-crystallins affect their structure, oligomerization, and chaperone function. Mutations in α-crystallins can lead to the aggregation/intracellular inclusions attributable to the perturbation of structure and oligomeric assembly and resulting in the rearrangement of aggregation-prone regions. Such rearrangements can lead to the exposure of hitherto buried aggregation-prone regions, thereby populating aggregation-prone state(s) and facilitating amorphous/amyloid aggregation and/or inappropriate interactions with cellular components. Investigations of the mutation-induced changes in the structure, oligomer assembly, aggregation mechanisms, and interactomes of α-crystallins will be useful in fighting protein aggregation-related diseases.
Topics: Cataract; Humans; Lens, Crystalline; Molecular Chaperones; Mutation; Protein Aggregates; alpha-Crystallins
PubMed: 35526854
DOI: 10.1134/S000629792203004X -
Journal of Insect Science (Online) 2015Heat shock proteins (HSPs) are abundant and ubiquitous in almost all organisms from bacteria to mammals. BmHSP20.8 is a small (sHSP) in Bombyx mori that contains a 561...
Heat shock proteins (HSPs) are abundant and ubiquitous in almost all organisms from bacteria to mammals. BmHSP20.8 is a small (sHSP) in Bombyx mori that contains a 561 bp open reading frame that encodes a protein of 186 amino acid residues with a predicted molecular mass of 20.8 kDa. The subcellular localization prediction indicated that BmHSP20.8 is likely distributed in the mitochondria with a 51% probability. To identify the subcellular localization of BmHSP20.8, three recombinant vectors were constructed and used to transfect BmN cells. The cytoplasmic and mitochondrial proteins were extracted 72 h after transfection. The Western blot showed that recombinant BmHSP20.8 exists only in the mitochondria. To locate the mitochondrial localization signal domain of BmHSP20.8 more accurately, we cloned four truncated recombinant vectors. The Western blot analysis of the cytoplasmic and mitochondrial proteins showed that the mitochondrial localization signal domain of BmHSP20.8 is located between amino acids 143 to 186. We constructed the pETduet-HIS-SUMO-BmHSP20.8 vector and a soluble BmHSP20.8 was expressed. In a citrate synthase (CS) thermal aggregation experiment, we found that the recombinant BmHSP20.8 protein can protect CS from aggregating at 43 and 48 °C and thus exhibited molecular chaperone activity. Taken together, the results showed that BmHSP20.8 could be a mitochondrial protein and has a molecular chaperone activity, suggesting an important role in mitochondria.
Topics: Animals; Bombyx; Gene Expression Regulation; HSP20 Heat-Shock Proteins; Insect Proteins; Molecular Chaperones; Sequence Analysis, Protein
PubMed: 26175462
DOI: 10.1093/jisesa/iev078 -
Trends in Biochemical Sciences Jul 2010The telomere environment requires an efficient means to assemble and disassemble a multitude of structures to operate correctly and to help achieve cellular homeostasis.... (Review)
Review
The telomere environment requires an efficient means to assemble and disassemble a multitude of structures to operate correctly and to help achieve cellular homeostasis. Telomeres are challenged by a common binding specificity displayed by many of the protein components for telomeric DNA, which could result in competitive DNA interactions, and by a cell cycle-restricted timing of events, which enforces a narrow working period in which to perform numerous tasks. In this review, we discuss how the HSP90 molecular chaperone network avoids these obstacles and facilitates an effective operation of the telomere system.
Topics: DNA; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Telomere
PubMed: 20236825
DOI: 10.1016/j.tibs.2010.02.005