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Science China. Life Sciences Feb 2022Mitochondria, double-membrane organelles, are known to participate in a variety of metabolic and signal transduction pathways. The intermembrane space (IMS) of...
Mitochondria, double-membrane organelles, are known to participate in a variety of metabolic and signal transduction pathways. The intermembrane space (IMS) of mitochondria is proposed to subject to multiple damages emanating from the respiratory chain. The optic atrophy 1 (OPA1), an important protein for mitochondrial fusion, is cleaved into soluble short-form (S-OPA1) under stresses. Here we report that S-OPA1 could function as a molecular chaperone in IMS. We purified the S-OPA1 (amino acid sequence after OPA1 isoform 5 S1 site) protein and showed it protected substrate proteins from thermally and chemically induced aggregation and strengthened the thermotolerance of Escherichia coli (E. coli). We also showed that S-OPA1 conferred thermotolerance on IMS proteins, e.g., neurolysin. The chaperone activity of S-OPA1 may be required for maintaining IMS homeostasis in mitochondria.
Topics: Escherichia coli; Escherichia coli Proteins; GTP Phosphohydrolases; Homeostasis; Metalloendopeptidases; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Molecular Chaperones; Protein Isoforms; Recombinant Proteins; Thermotolerance
PubMed: 34480695
DOI: 10.1007/s11427-021-1962-0 -
Cardiovascular Research Jun 2014Despite major advances in the treatment of cardiac diseases, there is still a great need for drugs capable of counteracting the deterioration of cardiac muscle function... (Review)
Review
Despite major advances in the treatment of cardiac diseases, there is still a great need for drugs capable of counteracting the deterioration of cardiac muscle function in congestive heart failure. The role of misfolded protein accumulation as a causal event in the physiopathology of common cardiac diseases is an important emerging concept. Indeed, diverse stress conditions, including mechanical stretching and oxidative stress, can induce misfolded protein accumulation, causing cardiomyocyte death. Cells react to these stress conditions by activating molecular chaperones, a class of proteins that represents an endogenous salvage machinery, essential for rescuing physiological cell functions and sustaining cell survival. Chaperones, also known as heat shock proteins (Hsps), prevent accumulation of damaged proteins by promoting either their refolding or degradation via the proteasome or the autophagosome systems. In addition, molecular chaperones play a key role in intracellular signalling by controlling conformational changes required for activation/deactivation of signalling proteins, and their assembly in specific signalosome complexes. The key role of molecular chaperones in heart function is highlighted by the fact that a number of genetic mutations in chaperone proteins result in different forms of cardiomyopathies. Moreover, a considerable amount of experimental evidence indicates that increasing expression of chaperone proteins leads to an important cardio-protective role in ischaemia/reperfusion injury, heart failure, and arrhythmia, implicating these molecules as potential innovative therapeutic agents.
Topics: Animals; Endoplasmic Reticulum Stress; Heart Diseases; Heat-Shock Proteins; Humans; Molecular Chaperones; Myocardial Reperfusion Injury; Protein Folding; Signal Transduction; Triage; Ventricular Remodeling
PubMed: 24585203
DOI: 10.1093/cvr/cvu049 -
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 Endocrinology Jan 2009Molecular chaperones are best recognized for their roles in de novo protein folding and the cellular response to stress. However, many molecular chaperones, and in... (Review)
Review
Molecular chaperones are best recognized for their roles in de novo protein folding and the cellular response to stress. However, many molecular chaperones, and in particular the Hsp70 chaperone machinery, have multiple diverse cellular functions. At the molecular level, chaperones are mediators of protein conformational change. To facilitate conformational change of client/substrate proteins, in manifold contexts, chaperone power must be closely regulated and harnessed to specific cellular locales--this is controlled by cochaperones. This review considers specialized functions of the Hsp70 chaperone machinery mediated by its cochaperones. We focus on vesicular trafficking, protein degradation and a potential role in G protein-coupled receptor processing.
Topics: Animals; Endocytosis; Exocytosis; HSP70 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Chaperones; Proteasome Endopeptidase Complex; Protein Conformation; Protein Folding; Receptors, G-Protein-Coupled
PubMed: 18852216
DOI: 10.1677/JME-08-0116 -
Methods in Molecular Biology (Clifton,... 2000
Review
Topics: Animals; Humans; Molecular Chaperones
PubMed: 10909095
DOI: 10.1385/1-59259-054-3:393 -
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 -
Pharmacology & Therapeutics Aug 1998The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90-kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major... (Review)
Review
The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90-kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major molecular chaperones of the cytosol and of the endoplasmic reticulum, respectively) has become an increasingly active subject of research in the past couple of years. These ubiquitous, well-conserved proteins account for 1-2% of all cellular proteins in most cells. However, their precise function is still far from being elucidated. Their involvement in the aetiology of several autoimmune diseases, in various infections, in recognition of malignant cells, and in antigen-presentation already demonstrates the essential role they likely will play in clinical practice of the next decade. The present review summarizes our current knowledge about the cellular functions, expression, and clinical implications of the 90-kDa molecular chaperone family and some approaches for future research.
Topics: Animals; Autoimmune Diseases; Cell Nucleus; Cytoskeleton; Cytosol; Diabetes Mellitus; Gene Expression Regulation; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Infections; Ischemia; Membrane Proteins; Molecular Chaperones; Neoplasms
PubMed: 9749880
DOI: 10.1016/s0163-7258(98)00013-8 -
Journal of Structural Biology Aug 2012The AAA(+)-ATPases are a family of molecular motors which have been seconded into a plethora of cellular tasks. One subset, the Hsp100 molecular chaperones, are general... (Review)
Review
The AAA(+)-ATPases are a family of molecular motors which have been seconded into a plethora of cellular tasks. One subset, the Hsp100 molecular chaperones, are general protein remodellers that help to maintain the integrity of the cellular proteome by means of protein destruction or resurrection. In this review we focus on one family of Hsp100s, the homologous ClpB and Hsp104 molecular chaperones that convey thermotolerance by resolubilising and rescuing proteins from aggregates. We explore how the nucleotide binding and hydrolysis properties at the twelve nucleotide-binding domains of these hexameric rings are coupled to protein disaggregation, highlighting similarities and differences between ClpB and Hsp104.
Topics: Endopeptidase Clp; Escherichia coli Proteins; Heat-Shock Proteins; Molecular Chaperones
PubMed: 22659404
DOI: 10.1016/j.jsb.2012.05.015 -
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 -
Cellular and Molecular Life Sciences :... Oct 2002The conserved heat shock protein Hsp33 functions as a potent molecular chaperone with a highly sophisticated regulation. On transcriptional level, the Hsp33 gene is... (Review)
Review
The conserved heat shock protein Hsp33 functions as a potent molecular chaperone with a highly sophisticated regulation. On transcriptional level, the Hsp33 gene is under heat shock control; on posttranslational level, the Hsp33 protein is under oxidative stress control. This dual regulation appears to reflect the close but rather neglected connection between heat shock and oxidative stress. The redox sensor in Hsp33 is a cysteine center that coordinates zinc under reducing, inactivating conditions and that forms two intramolecular disulfide bonds under oxidizing, activating conditions. Hsp33's redox-regulated chaperone activity appears to specifically protect proteins and cells from the otherwise deleterious effects of reactive oxygen species. That redox regulation of chaperone activity is not restricted to Hsp33 became evident when the chaperone activity of protein disulfide isomerase was recently also shown to cycle between a low- and high-affinity substrate binding state, depending on the redox state of its cysteines.
Topics: Amino Acid Sequence; Bacterial Proteins; Binding Sites; Dimerization; Escherichia coli Proteins; Heat-Shock Proteins; Models, Molecular; Molecular Chaperones; Oxidation-Reduction; Protein Conformation
PubMed: 12475172
DOI: 10.1007/pl00012489