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RNA Biology Dec 2016Recently, we found that RNA is a remarkably powerful chaperone that can bind to unfolded proteins and transfer them to Hsp70 for refolding. Combined with past studies on...
Recently, we found that RNA is a remarkably powerful chaperone that can bind to unfolded proteins and transfer them to Hsp70 for refolding. Combined with past studies on RNA-chaperone interactions, we propose a model for how chaperone RNA activity may contribute to the cellular response to stress.
Topics: HSP70 Heat-Shock Proteins; Models, Molecular; Molecular Chaperones; Protein Folding; Proteins; RNA; Stress, Physiological
PubMed: 27791471
DOI: 10.1080/15476286.2016.1247147 -
The Journal of Biological Chemistry 2021This review contains a personal account of the role played by the PDB in the development of the field of molecular chaperones and protein homeostasis, from the viewpoint... (Review)
Review
This review contains a personal account of the role played by the PDB in the development of the field of molecular chaperones and protein homeostasis, from the viewpoint of someone who experienced the concurrent advances in the structural biology, electron microscopy, and chaperone fields. The emphasis is on some key structures, including those of Hsp70, GroEL, Hsp90, and small heat shock proteins, that were determined as the molecular chaperone concept and systems for protein quality control were emerging. These structures were pivotal in demonstrating how seemingly nonspecific chaperones could assist the specific folding pathways of a variety of substrates. Moreover, they have provided mechanistic insights into the ATPase machinery of complexes such as GroEL/GroES that promote unfolding and folding and the disaggregases that extract polypeptides from large aggregates and disassemble amyloid fibers. The PDB has provided a framework for the current success in curating, evaluating, and distributing structural biology data, through both the PDB and the EMDB.
Topics: Animals; Chaperonin 10; Chaperonin 60; Databases, Protein; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Proteolysis
PubMed: 33957121
DOI: 10.1016/j.jbc.2021.100744 -
International Journal of Molecular... Feb 2022Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain... (Review)
Review
Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain proteins, which involves multiple steps of segmental folding, is one of the biggest questions in protein science. Multidomain protein folding often requires the assistance of molecular chaperones. Molecular chaperones promote or delay the folding of the client protein, but the detailed mechanisms are still unclear. This review summarizes the findings of biophysical and structural studies on the mechanism of multidomain protein folding mediated by molecular chaperones and explains how molecular chaperones recognize the client proteins and alter their folding properties. Furthermore, we introduce several recent studies that describe the concept of kinetics-activity relationships to explain the mechanism of functional diversity of molecular chaperones.
Topics: Humans; Kinetics; Molecular Chaperones; Protein Folding
PubMed: 35269628
DOI: 10.3390/ijms23052485 -
Protein Science : a Publication of the... Feb 2020As one of the most abundant and highly conserved molecular chaperones, the 70-kDa heat shock proteins (Hsp70s) play a key role in maintaining cellular protein... (Review)
Review
As one of the most abundant and highly conserved molecular chaperones, the 70-kDa heat shock proteins (Hsp70s) play a key role in maintaining cellular protein homeostasis (proteostasis), one of the most fundamental tasks for every living organism. In this role, Hsp70s are inextricably linked to many human diseases, most notably cancers and neurodegenerative diseases, and are increasingly recognized as important drug targets for developing novel therapeutics for these diseases. Hsp40s are a class of essential and universal partners for Hsp70s in almost all aspects of proteostasis. Thus, Hsp70s and Hsp40s together constitute one of the most important chaperone systems across all kingdoms of life. In recent years, we have witnessed significant progress in understanding the molecular mechanism of this chaperone system through structural and functional analysis. This review will focus on this recent progress, mainly from a structural perspective.
Topics: HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 31509306
DOI: 10.1002/pro.3725 -
Trends in Cell Biology Jan 2023The J-domain proteins (JDP) form the largest protein family among cellular chaperones. In cooperation with the Hsp70 chaperone system, these co-chaperones orchestrate a... (Review)
Review
The J-domain proteins (JDP) form the largest protein family among cellular chaperones. In cooperation with the Hsp70 chaperone system, these co-chaperones orchestrate a plethora of distinct functions, including those that help maintain cellular proteostasis and development. JDPs evolved largely through the fusion of a J-domain with other protein subdomains. The highly conserved J-domain facilitates the binding and activation of Hsp70s. How JDPs (re)wire Hsp70 chaperone circuits and promote functional diversity remains insufficiently explained. Here, we discuss recent advances in our understanding of the JDP family with a focus on the regulation built around J-domains to ensure correct pairing and assembly of JDP-Hsp70 machineries that operate on different clientele under various cellular growth conditions.
Topics: Humans; HSP40 Heat-Shock Proteins; Proteostasis; Molecular Chaperones; HSP70 Heat-Shock Proteins; Protein Binding
PubMed: 35729039
DOI: 10.1016/j.tcb.2022.05.004 -
Protein Science : a Publication of the... Aug 2022Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and...
Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and aggregation, are established, those specialized to work in the extracellular environment are less understood. Extracellular proteins reside in a considerably more oxidizing milieu than cytoplasmic proteins and are stabilized by abundant disulfide bonds. Hence, extracellular proteins are potentially destabilized and sensitive to aggregation under reducing conditions. We combine biochemical and mass spectrometry experiments and elucidate that the molecular chaperone functions of the extracellular protein domain Bri2 BRICHOS only appear under reducing conditions, through the assembly of monomers into large polydisperse oligomers by an intra- to intermolecular disulfide bond relay mechanism. Chaperone-active assemblies of the Bri2 BRICHOS domain are efficiently generated by physiological thiol-containing compounds and proteins, and appear in parallel with reduction-induced aggregation of extracellular proteins. Our results give insights into how potent chaperone activity can be generated from inactive precursors under conditions that are destabilizing to most extracellular proteins and thereby support protein stability/folding in the extracellular space. SIGNIFICANCE: Chaperones are essential to cells as they counteract toxic consequences of protein misfolding particularly under stress conditions. Our work describes a novel activation mechanism of an extracellular molecular chaperone domain, called Bri2 BRICHOS. This mechanism is based on reducing conditions that initiate small subunits to assemble into large oligomers via a disulfide relay mechanism. Activated Bri2 BRICHOS inhibits reduction-induced aggregation of extracellular proteins and could be a means to boost proteostasis in the extracellular environment upon reductive stress.
Topics: Adenosine Triphosphate; Disulfides; Molecular Chaperones; Protein Domains; Protein Folding
PubMed: 35900025
DOI: 10.1002/pro.4378 -
Biomolecules Apr 2022Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by... (Review)
Review
Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by which Hsp90 achieves such activation, involving structurally diverse client proteins, has remained enigmatic. However, recent advances using structural techniques, together with advances in biochemical studies, have not only defined the chaperone cycle but have shed light on its mechanism of action. Hsp90 hydrolysis of ATP by each protomer may not be simultaneous and may be dependent on the specific client protein and co-chaperone complex involved. Surprisingly, Hsp90 appears to remodel client proteins, acting as a means by which the structure of the client protein is modified to allow its subsequent refolding to an active state, in the case of kinases, or by making the client protein competent for hormone binding, as in the case of the GR (glucocorticoid receptor). This review looks at selected examples of client proteins, such as CDK4 (cyclin-dependent kinase 4) and GR, which are activated according to the so-called 'remodelling hypothesis' for their activation. A detailed description of these activation mechanisms is paramount to understanding how Hsp90-associated diseases develop.
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Receptors, Glucocorticoid
PubMed: 35625528
DOI: 10.3390/biom12050600 -
Biomolecules Aug 2022The highly conserved molecular chaperone heat shock protein 90 (Hsp90) is well-known for maintaining metastable proteins and mediating various aspects of intracellular... (Review)
Review
The highly conserved molecular chaperone heat shock protein 90 (Hsp90) is well-known for maintaining metastable proteins and mediating various aspects of intracellular protein dynamics. Intriguingly, high-throughput interactome studies suggest that Hsp90 is associated with a variety of other pathways. Here, we will highlight the potential impact of Hsp90 in protein transport. Currently, a limited number of studies have defined a few mechanistic contributions of Hsp90 to protein transport, yet the relevance of hundreds of additional connections between Hsp90 and factors known to aide this process remains unresolved. These interactors broadly support transport pathways including endocytic and exocytic vesicular transport, the transfer of polypeptides across membranes, or unconventional protein secretion. In resolving how Hsp90 contributes to the protein transport process, new therapeutic targets will likely be obtained for the treatment of numerous human health issues, including bacterial infection, cancer metastasis, and neurodegeneration.
Topics: Cytosol; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Transport
PubMed: 36008972
DOI: 10.3390/biom12081077 -
International Journal of Molecular... Oct 2019Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form... (Review)
Review
Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form aggregates, which are the main hallmark of many diseases including cancers, neurodegenerative diseases and many others. Proteins that assist other proteins in proper folding into three-dimensional structures are chaperones and co-chaperones. The key role of chaperones/co-chaperones is to prevent protein aggregation, especially under stress. An imbalance between chaperone/co-chaperone levels has been documented in neurons, and suggested to contribute to protein misfolding. An essential protein and a major regulator of protein folding in all eukaryotic cells is the heat shock protein 90 (Hsp90). The function of Hsp90 is tightly regulated by many factors, including co-chaperones. In this review we summarize results regarding the role of Hsp90 and its co-chaperones in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prionopathies.
Topics: Animals; Biomarkers; Disease Susceptibility; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neurodegenerative Diseases; Signal Transduction
PubMed: 31600883
DOI: 10.3390/ijms20204976 -
Cold Spring Harbor Perspectives in... Feb 2017Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based... (Review)
Review
Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based heritable elements that serve as an excellent experimental system for studying prion biology. The propagation of yeast prions is controlled by the same Hsp104/70/40 chaperone machinery that is involved in the protection of yeast cells against proteotoxic stress. Ribosome-associated chaperones, proteolytic pathways, cellular quality-control compartments, and cytoskeletal networks influence prion formation, maintenance, and toxicity. Environmental stresses lead to asymmetric prion distribution in cell divisions. Chaperones and cytoskeletal proteins mediate this effect. Overall, this is an intimate relationship with the protein quality-control machinery of the cell, which enables prions to be maintained and reproduced. The presence of many of these same mechanisms in higher eukaryotes has implications for the diagnosis and treatment of mammalian amyloid diseases.
Topics: Heat-Shock Proteins; Molecular Chaperones; Prions; Yeasts
PubMed: 27815300
DOI: 10.1101/cshperspect.a023663