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Free Radical Biology & Medicine Feb 2022Molecular chaperones are a family of proteins that maintain cellular protein homeostasis through non-covalent peptide folding and quality control mechanisms. The... (Review)
Review
Molecular chaperones are a family of proteins that maintain cellular protein homeostasis through non-covalent peptide folding and quality control mechanisms. The chaperone proteins found within mitochondria play significant protective roles in mitochondrial biogenesis, quality control, and stress response mechanisms. Defective mitochondrial chaperones have been implicated in aging, neurodegeneration, and cancer. In this review, we focus on the two most prominent mitochondrial chaperones: mtHsp60 and mtHsp70. These proteins demonstrate different cellular localization patterns, interact with different targets, and have different functional activities. We discuss the structure and function of these prominent mitochondrial chaperone proteins and give an update on newly discovered regulatory mechanisms and disease implications.
Topics: HSP70 Heat-Shock Proteins; Humans; Mitochondria; Mitochondrial Proteins; Molecular Chaperones; Protein Folding
PubMed: 34780988
DOI: 10.1016/j.freeradbiomed.2021.11.015 -
Biomolecules Aug 2022The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two... (Review)
Review
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications.
Topics: Animals; HSP90 Heat-Shock Proteins; Mice; Molecular Chaperones; Protein Isoforms; Proteome
PubMed: 36139005
DOI: 10.3390/biom12091166 -
Molecular Cell Jun 2021From biosynthesis to assembly into nucleosomes, histones are handed through a cascade of histone chaperones, which shield histones from non-specific interactions....
From biosynthesis to assembly into nucleosomes, histones are handed through a cascade of histone chaperones, which shield histones from non-specific interactions. Whether mechanisms exist to safeguard the histone fold during histone chaperone handover events or to release trapped intermediates is unclear. Using structure-guided and functional proteomics, we identify and characterize a histone chaperone function of DNAJC9, a heat shock co-chaperone that promotes HSP70-mediated catalysis. We elucidate the structure of DNAJC9, in a histone H3-H4 co-chaperone complex with MCM2, revealing how this dual histone and heat shock co-chaperone binds histone substrates. We show that DNAJC9 recruits HSP70-type enzymes via its J domain to fold histone H3-H4 substrates: upstream in the histone supply chain, during replication- and transcription-coupled nucleosome assembly, and to clean up spurious interactions. With its dual functionality, DNAJC9 integrates ATP-resourced protein folding into the histone supply pathway to resolve aberrant intermediates throughout the dynamic lives of histones.
Topics: Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly; DNA Replication; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HeLa Cells; Histone Chaperones; Histones; Humans; Minichromosome Maintenance Complex Component 2; Models, Molecular; Molecular Chaperones; Nucleosomes; Protein Binding; Proteomics
PubMed: 33857403
DOI: 10.1016/j.molcel.2021.03.041 -
Journal of Molecular Histology Apr 2023The chaperone system (CS) of an organism is composed of molecular chaperones, chaperone co-factors, co-chaperones, and chaperone receptors and interactors. It is present... (Review)
Review
The chaperone system (CS) of an organism is composed of molecular chaperones, chaperone co-factors, co-chaperones, and chaperone receptors and interactors. It is present throughout the body but with distinctive features for each cell and tissue type. Previous studies pertaining to the CS of the salivary glands have determined the quantitative and distribution patterns for several members, the chaperones, in normal and diseased glands, focusing on tumors. Chaperones are cytoprotective, but can also be etiopathogenic agents causing diseases, the chaperonopathies. Some chaperones such as Hsp90 potentiate tumor growth, proliferation, and metastasization. Quantitative data available on this chaperone in salivary gland tissue with inflammation, and benign and malignant tumors suggest that assessing tissue Hsp90 levels and distribution patterns is useful for differential diagnosis-prognostication, and patient follow up. This, in turn, will reveal clues for developing specific treatment centered on the chaperone, for instance by inhibiting its pro-carcinogenic functions (negative chaperonotherapy). Here, we review data on the carcinogenic mechanisms of Hsp90 and their inhibitors. Hsp90 is the master regulator of the PI3K-Akt-NF-kB axis that promotes tumor cell proliferation and metastasization. We discuss pathways and interactions involving these molecular complexes in tumorigenesis and review Hsp90 inhibitors that have been tested in search of an efficacious anti-cancer agent. This targeted therapy deserves extensive investigation in view of its theoretical potential and some positive practical results and considering the need of novel treatments for tumors of the salivary glands as well as other tissues.
Topics: Humans; Phosphatidylinositol 3-Kinases; Molecular Chaperones; HSP90 Heat-Shock Proteins; Neoplasms
PubMed: 36933095
DOI: 10.1007/s10735-023-10119-8 -
Journal of Molecular Biology Sep 2015Hsp90 is a molecular chaperone that facilitates the maturation of signaling proteins including many kinases and steroid hormone receptors. Through these client proteins,... (Review)
Review
Hsp90 is a molecular chaperone that facilitates the maturation of signaling proteins including many kinases and steroid hormone receptors. Through these client proteins, Hsp90 is a key mediator of many physiological processes and has emerged as a promising drug target in cancer. Additionally, Hsp90 can mask or potentiate the impact of mutations in clients with remarkable influence on evolutionary adaptations. The influential roles of Hsp90 in biology and disease have stimulated extensive research into the molecular mechanism of this chaperone. These studies have shown that Hsp90 is a homodimeric protein that requires ATP hydrolysis and a host of accessory proteins termed co-chaperones to facilitate the maturation of clients to their active states. Flexible hinge regions between its three structured domains enable Hsp90 to sample dramatically distinct conformations that are influenced by nucleotide, client, and co-chaperone binding. While it is clear that Hsp90 can exist in symmetrical conformations, recent studies have indicated that this homodimeric chaperone can also assume a variety of asymmetric conformations and complexes that are important for client maturation. The visualization of Hsp90-client complexes at high resolution together with tools to independently manipulate each subunit in the Hsp90 dimer are providing new insights into the asymmetric function of each subunit during client maturation.
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Hydrolysis; Molecular Chaperones; Mutation; Nucleotides; Protein Binding; Protein Conformation; Protein Multimerization; Signal Transduction
PubMed: 25843003
DOI: 10.1016/j.jmb.2015.03.017 -
FEBS Letters Jul 2023Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and... (Review)
Review
Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post-translational modifications and metabolite-based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.
Topics: Humans; Protein Folding; Molecular Chaperones; HSP90 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Processing, Post-Translational
PubMed: 37287189
DOI: 10.1002/1873-3468.14682 -
Medicinal Research Reviews Nov 2022The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic... (Review)
Review
The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic reticulum (ER) stress and disease. Grp94 belongs to the Hsp90 family of molecular chaperones and is a master regulator of ER homeostasis due to its ability to fold and stabilize proteins/receptors, and to chaperone misfolded proteins for degradation. Multiple studies have demonstrated that Grp94 knockdown or inhibition leads to the degradation of client protein substrates, which leads to disruption of disease-dependent signaling pathways. As a result, small molecule inhibitors of Grp94 have become a promising therapeutic approach to target a variety of disease states. Specifically, Grp94 has proven to be a promising target for cancer, glaucoma, immune-mediated inflammation, and viral infection. Moreover, Grp94-peptide complexes have been utilized effectively as adjuvants for vaccines against a variety of disease states. This work highlights the significance of Grp94 biology and the development of therapeutics that target this molecular chaperone in multiple disease states.
Topics: Biology; HSP70 Heat-Shock Proteins; Humans; Membrane Glycoproteins; Membrane Proteins; Molecular Chaperones
PubMed: 35861260
DOI: 10.1002/med.21915 -
The Journal of Biological Chemistry Feb 2019The molecular chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and... (Review)
Review
The molecular chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and with their "client" proteins. Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation. The core chaperones, such as the heat shock proteins Hsp60, Hsp70, and Hsp90, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This possibility suggests that these PPIs, and perhaps not the individual chaperones themselves, could be compelling drug targets. Indeed, recent efforts have yielded small molecules that inhibit (or promote) a subset of inter-chaperone PPIs. These chemical probes are being used to study chaperone networks in a range of models, and the successes with these approaches have inspired a community-wide objective to produce inhibitors for a broader set of targets. In this Review, we discuss progress toward that goal and point out some of the challenges ahead.
Topics: Animals; Chaperonin 60; Enzyme Inhibitors; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Protein Interaction Maps; Proteostasis
PubMed: 30213856
DOI: 10.1074/jbc.TM118.002813 -
The Journal of Biological Chemistry Feb 2023An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular... (Review)
Review
An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular milieu face numerous challenges that can lead to protein misfolding and aggregation. As a checkpoint for proteins that move between cells, extracellular chaperone networks are of growing clinical relevance. J-domain proteins (JDPs) are ubiquitous molecular chaperones that are known for their essential roles in a wide array of fundamental cellular processes through their regulation of heat shock protein 70s. As the largest molecular chaperone family, JDPs have long been recognized for their diverse functions within cells. Some JDPs are elegantly selective for their "client proteins," some do not discriminate among substrates and others act cooperatively on the same target. The realization that JDPs are exported through both classical and unconventional secretory pathways has fueled investigation into the roles that JDPs play in protein quality control and intercellular communication. The proposed functions of exported JDPs are diverse. Studies suggest that export of DnaJB11 enhances extracellular proteostasis, that intercellular movement of DnaJB1 or DnaJB6 enhances the proteostasis capacity in recipient cells, whereas the import of DnaJB8 increases resistance to chemotherapy in recipient cancer cells. In addition, the export of DnaJC5 and concurrent DnaJC5-dependent ejection of dysfunctional and aggregation-prone proteins are implicated in the prevention of neurodegeneration. This review provides a brief overview of the current understanding of the extracellular chaperone networks and outlines the first wave of studies describing the cellular export of JDPs.
Topics: Humans; Molecular Chaperones; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Proteostasis; Nerve Tissue Proteins
PubMed: 36581212
DOI: 10.1016/j.jbc.2022.102840 -
Journal of Molecular Biology Sep 2018The molecular chaperone Hsp90 is involved in the folding, maturation, and degradation of a large number structurally and sequentially unrelated clients, often connected... (Review)
Review
The molecular chaperone Hsp90 is involved in the folding, maturation, and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognizes this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of proteins. Hsp90 acts downstream of the chaperone Hsp70, which exposes its substrate to a short and highly hydrophobic cleft. The subsequently acting Hsp90 has an extended client-binding interface that enables a large number of low-affinity contacts. Structural studies show interaction modes of Hsp90 with the intrinsically disordered Alzheimer's disease-causing protein Tau, the kinase Cdk4 in a partially unfolded state and the folded ligand-binding domain of a steroid receptor. Comparing the features shared by these different proteins provides a picture of the substrate-binding principles of Hsp90.
Topics: Animals; Binding Sites; Carrier Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Chaperones; Protein Binding; Protein Interaction Domains and Motifs; Structure-Activity Relationship
PubMed: 29782836
DOI: 10.1016/j.jmb.2018.05.026