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International Journal of Molecular... Apr 2021Thyroid 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... (Review)
Review
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.
Topics: Animals; Chaperonin 60; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Thyroid Neoplasms
PubMed: 33919591
DOI: 10.3390/ijms22084196 -
Cold Spring Harbor Perspectives in... Oct 2019Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis... (Review)
Review
Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis process within the nucleus is limited. Here, we discuss the identified roles of the major molecular chaperones Hsp90, Hsp70, and Hsp60 with client proteins working in diverse DNA-associated pathways. The unique challenges facing proteins in the nucleus are considered as well as the conserved features of the molecular chaperone system in facilitating DNA-linked processes. As nuclear protein inclusions are a common feature of protein-aggregation diseases (e.g., neurodegeneration), a better understanding of nuclear proteostasis is warranted.
Topics: Cell Nucleus; DNA; Humans; Molecular Chaperones; Nuclear Proteins
PubMed: 30745291
DOI: 10.1101/cshperspect.a034009 -
The Journal of Membrane Biology Dec 2020Spectrin is a multifunctional, multi-domain protein most well known in the membrane skeleton of mature human erythrocytes. Here we review the literature on the crosstalk... (Review)
Review
Spectrin is a multifunctional, multi-domain protein most well known in the membrane skeleton of mature human erythrocytes. Here we review the literature on the crosstalk of the chaperone activity of spectrin with its other functionalities. We hypothesize that the chaperone activity is derived from the surface exposed hydrophobic patches present in individual "spectrin-repeat" domains and show a competition between the membrane phospholipid binding functionality and chaperone activity of spectrin. Moreover, we show that post-translational modifications such as glycation which shield these surface exposed hydrophobic patches, reduce the chaperone function. On the other hand, oligomerization which is linked to increase of hydrophobicity is seen to increase it. We note that spectrin seems to prefer haemoglobin as its chaperone client, binding with it preferentially over other denatured proteins. Spectrin is also known to interact with unstable haemoglobin variants with a higher affinity than in the case of normal haemoglobin. We propose that chaperone activity of spectrin could be important in the cellular biochemistry of haemoglobin, particularly in the context of diseases.
Topics: Animals; Erythrocyte Membrane; Hemoglobins; Humans; Hydrophobic and Hydrophilic Interactions; Membrane Proteins; Molecular Chaperones; Phospholipids; Protein Binding; Protein Processing, Post-Translational; Spectrin
PubMed: 32990795
DOI: 10.1007/s00232-020-00142-1 -
Sub-cellular Biochemistry 2023The co-chaperone p50/Cdc37 is an important partner for Hsp90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases....
The co-chaperone p50/Cdc37 is an important partner for Hsp90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Analysis of the structure of Hsp90-Cdc37-kinase complexes demonstrates the way in which Cdc37 interacts with and controls the folding of a large proportion of intracellular protein kinases. This co-chaperone thus stands at the hub of a multitude of intracellular signaling networks. Indeed, the influence of Cdc37 reaches beyond the housekeeping pathways of protein folding into the regulation of a wide range of cellular processes. This co-chaperone has attracted attention as a potential intermediate in carcinogenesis. Cdc37 is an attractive potential target in cancer due to (1) high expression in a number of tumor types and (2) control of multiple signaling pathways. These properties indicate (3) a potential for selectivity due to its elevated expression in malignant cells and (4) robustness, as the co-chaperone may control multiple growth signaling pathways and thus be less prone to evolution of resistance than less versatile oncoproteins. Cdc37 may also be involved in other aspects of pathophysiology and has been shown to be secreted in exosomes. Protein aggregation disorders have been linked to age-related declines in molecular chaperones and co-chaperones. Cdc37 also appears to be a potential agent in longevity due to its links to protein folding and autophagy, and it will be informative to study the role of Cdc37 maintenance/decline in aging organisms.
Topics: Chaperonins; Cell Cycle Proteins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Kinases; Protein Binding
PubMed: 36520306
DOI: 10.1007/978-3-031-14740-1_5 -
The Enzymes 2023Proteins are the most structurally diverse cellular biomolecules that act as molecular machines driving essential activities of all living organisms. To be functional,... (Review)
Review
Proteins are the most structurally diverse cellular biomolecules that act as molecular machines driving essential activities of all living organisms. To be functional, most of the proteins need to fold into a specific three-dimensional structure, which on one hand should be stable enough to oppose disruptive conditions and on the other hand flexible enough to allow conformational dynamics necessary for their biological functions. This compromise between stability and dynamics makes proteins susceptible to stress-induced misfolding and aggregation. Moreover, the folding process itself is intrinsically prone to conformational errors. Molecular chaperones are proteins that mitigate folding defects and maintain the structural integrity of the cellular proteome. Promiscuous Hsp70 chaperones are central to these processes and their activity depends on the interaction with obligatory J-domain protein (JDP) partners. In this review, we discuss structural aspects of Hsp70s, JDPs, and their interaction in the context of biological activities.
Topics: HSP70 Heat-Shock Proteins; Molecular Chaperones; Humans
PubMed: 37945173
DOI: 10.1016/bs.enz.2023.07.008 -
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 -
Sub-cellular Biochemistry 2023Cellular homeostasis and stress survival requires maintenance of the proteome and suppression of proteotoxicity. Molecular chaperones promote cell survival through... (Review)
Review
Cellular homeostasis and stress survival requires maintenance of the proteome and suppression of proteotoxicity. Molecular chaperones promote cell survival through repair of misfolded proteins and cooperation with protein degradation machines to discard terminally damaged proteins. Hsp70 family members play an essential role in cellular protein metabolism by binding and releasing non-native proteins to facilitate protein folding, refolding, and degradation. Hsp40 (DnaJ-like proteins) family members are Hsp70 co-chaperones that determine the fate of Hsp70 clients by facilitating protein folding, assembly, and degradation. Hsp40s select substrates for Hsp70 via use of an intrinsic chaperone activity to bind non-native regions of proteins. During delivery of bound cargo Hsp40s employ a conserved J-domain to stimulate Hsp70 ATPase activity and thereby stabilize complexes between Hsp70 and non-native proteins. This review describes the mechanisms by which different Hsp40s use specialized sub-domains to direct clients of Hsp70 for triage between folding versus degradation.
Topics: Humans; Homeostasis; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Molecular Chaperones; Protein Binding; Protein Folding; Proteolysis
PubMed: 36520305
DOI: 10.1007/978-3-031-14740-1_4 -
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