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Biomolecules Jul 2022Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been... (Review)
Review
Heat shock protein 90 (Hsp90) is one of the major guardians of cellular protein homeostasis, through its specialized molecular chaperone properties. While Hsp90 has been extensively studied in many prokaryotic and higher eukaryotic model organisms, its structural, functional, and biological properties in parasitic protozoans are less well defined. Hsp90 collaborates with a wide range of co-chaperones that fine-tune its protein folding pathway. Co-chaperones play many roles in the regulation of Hsp90, including selective targeting of client proteins, and the modulation of its ATPase activity, conformational changes, and post-translational modifications. is responsible for the most lethal form of human malaria. The survival of the malaria parasite inside the host and the vector depends on the action of molecular chaperones. The major cytosolic Hsp90 (PfHsp90) is known to play an essential role in the development of the parasite, particularly during the intra-erythrocytic stage in the human host. Although PfHsp90 shares significant sequence and structural similarity with human Hsp90, it has several major structural and functional differences. Furthermore, its co-chaperone network appears to be substantially different to that of the human host, with the potential absence of a key homolog. Indeed, PfHsp90 and its interface with co-chaperones represent potential drug targets for antimalarial drug discovery. In this review, we critically summarize the current understanding of the properties of Hsp90, and the associated co-chaperones of the malaria parasite.
Topics: HSP90 Heat-Shock Proteins; Humans; Malaria, Falciparum; Molecular Chaperones; Plasmodium falciparum
PubMed: 35892329
DOI: 10.3390/biom12081018 -
Cell Chemical Biology May 2022The molecular chaperone DnaK, is an attractive drug target for treating mycobacterial infections. In this issue, Hosfelt, Richards, and colleagues applied a...
The molecular chaperone DnaK, is an attractive drug target for treating mycobacterial infections. In this issue, Hosfelt, Richards, and colleagues applied a high-throughput screen and discovered inhibitors that disrupt cofactor-mediated activation of DnaK. These inhibitors can lower bacterial survival under stress and decrease resistance to key antibiotics.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Escherichia coli Proteins; HSP70 Heat-Shock Proteins; Molecular Chaperones
PubMed: 35594848
DOI: 10.1016/j.chembiol.2022.05.002 -
Brain & Development Jan 2021In lysosomal diseases, enzyme deficiency is caused by misfolding of mutant enzyme protein with abnormal steric structure that is expressed by gene mutation. Chaperone... (Review)
Review
In lysosomal diseases, enzyme deficiency is caused by misfolding of mutant enzyme protein with abnormal steric structure that is expressed by gene mutation. Chaperone therapy is a new molecular therapeutic approach primarily for lysosomal diseases. The misfolded mutant enzyme is digested rapidly or aggregated to induce endoplasmic reticulum stress. As a result, the catalytic activity is lost. The following sequence of events results in chaperone therapy to achieve correction of molecular pathology. An orally administered low molecular competitive inhibitor (chaperone) is absorbed into the bloodstream and reaches the target cells and tissues. The mutant enzyme is stabilized by the chaperone and subjected to normal enzyme proteinfolding (proteostasis). The first chaperone drug was developed for Fabry disease and is currently available in medical practice. At present three types of chaperones are available: competitive chaperone with enzyme inhibitory bioactivity (exogenous), non-competitive (or allosteric) chaperone without inhibitory bioactivity (exogenous), and molecular chaperone (heat shock protein; endogenous). The third endogenous chaperone would be directed to overexpression or activated by an exogenous low-molecular inducer. This new molecular therapeutic approach, utilizing the three types of chaperone, is expected to apply to a variety of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases.
Topics: Endoplasmic Reticulum Stress; Fabry Disease; Gangliosidosis, GM1; Humans; Lysosomal Storage Diseases; Lysosomes; Molecular Chaperones; Proteostasis Deficiencies
PubMed: 32736903
DOI: 10.1016/j.braindev.2020.06.015 -
Biopolymers Aug 2016The HSP90 molecular chaperone is involved in the activation and cellular stabilization of a range of 'client' proteins, of which oncogenic protein kinases and nuclear... (Review)
Review
The HSP90 molecular chaperone is involved in the activation and cellular stabilization of a range of 'client' proteins, of which oncogenic protein kinases and nuclear steroid hormone receptors are of particular biomedical significance. Work over the last two decades has revealed a conformational cycle critical to the biological function of HSP90, coupled to an inherent ATPase activity that is regulated and manipulated by many of the co-chaperones proteins with which it collaborates. Pharmacological inhibition of HSP90 ATPase activity results in degradation of client proteins in vivo, and is a promising target for development of new cancer therapeutics. Despite this, the actual function that HSP90s conformationally-coupled ATPase activity provides in its biological role as a molecular chaperone remains obscure. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 594-607, 2016.
Topics: Adenosine Triphosphatases; Animals; HSP90 Heat-Shock Proteins; Humans; Protein Conformation; Proteolysis
PubMed: 26991466
DOI: 10.1002/bip.22835 -
Brain & Development May 2023Chaperone therapy was introduced first as a new molecular therapeutic approach to lysosomal diseases. In a recent article, I reviewed the development of chaperone... (Review)
Review
Chaperone therapy was introduced first as a new molecular therapeutic approach to lysosomal diseases. In a recent article, I reviewed the development of chaperone therapy mainly for lysosomal diseases. Then, more data have been collected particularly on non-lysosomal protein misfolding diseases. In this short review, I propose the concept of chaperone therapy to be classified into two different therapeutic approaches, for pH-dependent lysosomal, and pH-independent non-lysosomal protein misfolding diseases. The concept of lysosomal chaperone therapy is well established, but the non-lysosomal chaperone therapy is heterogeneous and to be investigated further for various individual diseases. As a whole, these two-types of new molecular therapeutic approaches will make an impact on the treatment of a wide range of pathological conditions caused by protein misfolding, not necessarily lysosomal but also many non-lysosomal diseases caused by gene mutations, metabolic diseases, malignancy, infectious diseases, and aging. The concept will open a completely new aspect of protein therapy in future.
Topics: Humans; Molecular Chaperones; Proteostasis Deficiencies; Mutation; Lysosomes
PubMed: 36870919
DOI: 10.1016/j.braindev.2023.02.004 -
Journal of Medical Microbiology Mar 2017Heat shock proteins are highly conserved, stress-inducible, ubiquitous proteins that maintain homeostasis in both eukaryotes and prokaryotes. Hsp70 proteins belong to... (Review)
Review
Heat shock proteins are highly conserved, stress-inducible, ubiquitous proteins that maintain homeostasis in both eukaryotes and prokaryotes. Hsp70 proteins belong to the heat shock protein family and enhance bacterial survival in hostile environments. Hsp70, known as DnaK in prokaryotes, supports numerous processes such as the assembly and disassembly of protein complexes, the refolding of misfolded and clustered proteins, membrane translocation and the regulation of regulatory proteins. The chaperone-based activity of Hsp70 depends on dynamic interactions between its two domains, known as the ATPase domain and the substrate-binding domain. It also depends on interactions between these domains and other co-chaperone molecules such as the Hsp40 protein family member DnaJ and nucleotide exchange factors. DnaJ is the primary chaperone that interacts with nascent polypeptide chains and functions to prevent their premature release from the ribosome and misfolding before it is targeted by DnaK. Adhesion of bacteria to host cells is mediated by both host and bacterial Hsp70. Following infection of the host, bacterial Hsp70 (DnaK) is in a position to initiate bacterial survival processes and trigger an immune response by the host. Any mutations in the dnaK gene have been shown to decrease the viability of bacteria inside the host. This review will give insights into the structure and mechanism of Hsp70 and its role in regulating the protein activity that contributes to pathogenesis.
Topics: Adenosine Triphosphatases; Bacteria; Bacterial Adhesion; Bacterial Proteins; Escherichia coli; Escherichia coli Proteins; HSP70 Heat-Shock Proteins; Host-Pathogen Interactions; Immune Evasion; Molecular Chaperones; Protein Binding
PubMed: 28086078
DOI: 10.1099/jmm.0.000429 -
Trends in Cell Biology Feb 2019Conserved families of molecular chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous,... (Review)
Review
Conserved families of molecular chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous, chaperone-independent folding; (ii) folding assisted by repetitive Hsp70 cycles; and (iii) folding by the Hsp70-Hsp90 cascades. These chaperones prepare their protein clients for folding on their own, without altering their folding path. A particularly interesting role is reserved for Hsp90. The function of Hsp90 in folding is its ancient function downstream of Hsp70, free of cochaperone regulation and present in all kingdoms of life. Eukaryotic signalling networks, however, embrace Hsp90 by a plethora of cochaperones, transforming the profolding machinery to a folding-on-demand factor. We discuss implications for biology and molecular medicine.
Topics: Adenosine Triphosphate; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Chaperones; Protein Binding; Protein Conformation; Protein Folding; Proteostasis
PubMed: 30502916
DOI: 10.1016/j.tcb.2018.10.004 -
Trends in Biochemical Sciences Nov 2017Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, and severe... (Review)
Review
Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, and severe heat stress which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. We review here recent advances in identifying and characterizing stress-activated chaperones which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the post-translational mechanisms by which these chaperones sense stress, and consider the role that intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets.
Topics: Animals; Humans; Molecular Chaperones; Oxidative Stress; Protein Processing, Post-Translational; Protein Unfolding; Proteome
PubMed: 28893460
DOI: 10.1016/j.tibs.2017.08.006 -
Methods in Molecular Biology (Clifton,... 2023The molecular chaperone heat shock protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis....
The molecular chaperone heat shock protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis. There are multiple Hsp90 isoforms including the cytosolic Hsp90α and Hsp90β as well as GRP94 located in the endoplasmic reticulum and TRAP1 in the mitochondria. The chaperone function of Hsp90 is linked to its ability to bind and hydrolyze ATP. Co-chaperones and posttranslational modifications (such as phosphorylation, SUMOylation, and ubiquitination) are important for Hsp90 stability and regulation of its ATPase activity. Both mammalian and yeast cells can be used to express and purify Hsp90 and TRAP1 and also detect post-translational modifications by immunoblotting.
Topics: Animals; HSP90 Heat-Shock Proteins; Protein Processing, Post-Translational; Molecular Chaperones; Phosphorylation; Protein Isoforms; Ubiquitination; Saccharomyces cerevisiae; Mammals
PubMed: 37540432
DOI: 10.1007/978-1-0716-3342-7_11 -
Nature Structural & Molecular Biology Dec 2023Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR)....
Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation.
Topics: Humans; Receptors, Glucocorticoid; Cryoelectron Microscopy; Tacrolimus Binding Proteins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Binding
PubMed: 37945740
DOI: 10.1038/s41594-023-01128-y