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Annual Review of Biochemistry 2013The biological functions of proteins are governed by their three-dimensional fold. Protein folding, maintenance of proteome integrity, and protein homeostasis... (Review)
Review
The biological functions of proteins are governed by their three-dimensional fold. Protein folding, maintenance of proteome integrity, and protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)folding. Folding occurs upon controlled release of newly synthesized proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
Topics: Humans; Molecular Chaperones; Protein Folding; Proteins; Proteome; Proteostasis Deficiencies
PubMed: 23746257
DOI: 10.1146/annurev-biochem-060208-092442 -
The Hsp90 molecular chaperone governs client proteins by targeting intrinsically disordered regions.Molecular Cell Jun 2023Molecular chaperones govern proteome health to support cell homeostasis. An essential eukaryotic component of the chaperone system is Hsp90. Using a chemical-biology...
Molecular chaperones govern proteome health to support cell homeostasis. An essential eukaryotic component of the chaperone system is Hsp90. Using a chemical-biology approach, we characterized the features driving the Hsp90 physical interactome. We found that Hsp90 associated with ∼20% of the yeast proteome using its three domains to preferentially target intrinsically disordered regions (IDRs) of client proteins. Hsp90 selectively utilized an IDR to regulate client activity as well as maintained IDR-protein health by preventing the transition to stress granules or P-bodies at physiological temperatures. We also discovered that Hsp90 controls the fidelity of ribosome initiation that triggers a heat shock response when disrupted. Our study provides insights into how this abundant molecular chaperone supports a dynamic and healthy native protein landscape.
Topics: Humans; HSP90 Heat-Shock Proteins; Molecular Chaperones; Proteome; Saccharomyces cerevisiae; Intrinsically Disordered Proteins
PubMed: 37295430
DOI: 10.1016/j.molcel.2023.05.021 -
Bioconjugate Chemistry May 2020Molecular chaperones play critical roles in biological functions. They are closely involved in the maintenance of cell homeostasis, proper folding of proteins and... (Review)
Review
Molecular chaperones play critical roles in biological functions. They are closely involved in the maintenance of cell homeostasis, proper folding of proteins and nucleic acids, and inhibition of irreversible aggregation in denatured proteins. In addition to protein production, molecular chaperone function is widely recognized as important for peptide and protein drug delivery systems. Therefore, much effort has been made in recent decades to develop chaperone-mimetic molecules that have similar structures and biological functions to natural chaperones. These artificial molecular chaperone systems have been demonstrated to facilitate proper protein and nucleic acid folding, in addition to the formation of higher-order structures of synthetic molecules. Furthermore, the functions of these artificial systems show promising clinical applications in drug delivery and biomolecule detection. This topical review focuses on recent advances in the design, construction, characterization, and potential applications of different artificial molecular systems with distinct functional roles, such as the folding of water-soluble and membrane proteins, nucleic acids, and the self-assembly of synthetic molecules. Strategies used in the construction of some artificial molecule chaperone systems for proteins (such as pairs of amphiphilic molecules or self-assembled nanogels) and their applications as biomaterials are described. Specific examples from each design strategy are also highlighted to demonstrate the mechanisms, challenges, and limitations of the different artificial molecular systems. By highlighting the many new developments that have expanded the applications of the artificial chaperones beyond protein folding, this review aims to stimulate further studies on their design and applications.
Topics: Animals; Biomimetic Materials; Drug Design; Humans; Molecular Chaperones; Nucleic Acids; Protein Folding
PubMed: 32336086
DOI: 10.1021/acs.bioconjchem.0c00133 -
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 -
Accounts of Chemical Research Apr 2018Molecular chaperones play a central role in protein homeostasis (a.k.a. proteostasis) by balancing protein folding, quality control, and turnover. To perform these... (Review)
Review
Molecular chaperones play a central role in protein homeostasis (a.k.a. proteostasis) by balancing protein folding, quality control, and turnover. To perform these diverse tasks, chaperones need the malleability to bind nearly any "client" protein and the fidelity to detect when it is misfolded. Remarkably, these activities are carried out by only ∼180 dedicated chaperones in humans. How do a relatively small number of chaperones maintain cellular and organismal proteostasis for an entire proteome? Furthermore, once a chaperone binds a client, how does it "decide" what to do with it? One clue comes from observations that individual chaperones engage in protein-protein interactions (PPIs)-both with each other and with their clients. These physical links coordinate multiple chaperones into organized, functional complexes and facilitate the "handoff" of clients between them. PPIs also link chaperones and their clients to other cellular pathways, such as those that mediate trafficking (e.g., cytoskeleton) and degradation (e.g., proteasome). The PPIs of the chaperone network have a wide range of affinity values (nanomolar to micromolar) and involve many distinct types of domain modules, such as J domains, zinc fingers, and tetratricopeptide repeats. Many of these motifs have the same binding surfaces on shared partners, such that members of one chaperone class often compete for the same interactions. Somehow, this collection of PPIs draws together chaperone families and creates multiprotein subnetworks that are able to make the "decisions" of protein quality control. The key to understanding chaperone-mediated proteostasis might be to understand how PPIs are regulated. This Account will discuss the efforts of our group and others to map, measure, and chemically perturb the PPIs within the molecular chaperone network. Structural biology methods, including X-ray crystallography, NMR spectroscopy, and electron microscopy, have all played important roles in visualizing the chaperone PPIs. Guided by these efforts and -omics approaches to measure PPIs, new advances in high-throughput chemical screening that are specially designed to account for the challenges of this system have emerged. Indeed, chemical biology has played a particularly important role in this effort, as molecules that either promote or inhibit specific PPIs have proven to be invaluable research probes in cells and animals. In addition, these molecules have provided leads for the potential treatment of protein misfolding diseases. One of the major products of this research field has been the identification of putative PPI drug targets within the chaperone network, which might be used to change chaperone "decisions" and rebalance proteostasis.
Topics: Animals; Humans; Models, Molecular; Molecular Chaperones; Protein Binding; Protein Interaction Mapping
PubMed: 29613769
DOI: 10.1021/acs.accounts.8b00036 -
Life Sciences Aug 2020Tumor necrosis factor receptor-associated protein 1 (TRAP1), a molecular chaperone, is a major member of the mitochondrial heat shock protein 90 (Hsp90) family. Studies... (Review)
Review
Tumor necrosis factor receptor-associated protein 1 (TRAP1), a molecular chaperone, is a major member of the mitochondrial heat shock protein 90 (Hsp90) family. Studies have shown that TRAP1 can prevent hypoxia-induced damage to cardiomyocytes, maintain cardiomyocytes viability and mitochondrial membrane potential, and protect cardiomyocytes. In addition, it can also protect astrocytes from ischemic damage in vitro. In recent years, there have been many new discoveries in tumors. The abnormal expression of TRAP1 is closely related to the occurrence and development of various tumors. TRAP1 protein seems to be a central regulatory protein, involved in the activation of various oncogenic proteins and signaling pathways, and has a balanced function at tumor transformation and the intersection of different metabolic processes. Targeting its chaperone activity and molecular interactions can destroy the metabolism and survival adaptability of tumor cells, paving the way for the development of highly selective mitochondrial anti-tumor drugs. Moreover, the combination of TRAP1 inhibition and current traditional cancer therapies has shown promising applications. These findings have important implications for the diagnosis and treatment of tumors. Therefore, we reviewed the recently identified functions of the molecular chaperone TRAP1 in cancer development and progression, as well as the discovery and recent advances in selective TRAP1 inhibitors as anticancer drug therapies, opening up new attractive prospects for exploring strategies for targeting TRAP1 as a tumor cell target.
Topics: Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms
PubMed: 32376268
DOI: 10.1016/j.lfs.2020.117737 -
Biopolymers Nov 2013This review is focused on the mechanisms by which ATP binding and hydrolysis drive chaperone machines assisting protein folding and unfolding. A survey of the key,... (Review)
Review
This review is focused on the mechanisms by which ATP binding and hydrolysis drive chaperone machines assisting protein folding and unfolding. A survey of the key, general chaperone systems Hsp70 and Hsp90, and the unfoldase Hsp100 is followed by a focus on the Hsp60 chaperonin machine which is understood in most detail. Cryo-electron microscopy analysis of the E. coli Hsp60 GroEL reveals intermediate conformations in the ATPase cycle and in substrate folding. These structures suggest a mechanism by which GroEL can forcefully unfold and then encapsulate substrates for subsequent folding in isolation from all other binding surfaces.
Topics: Adenosine Triphosphate; Chaperonin 60; Escherichia coli; Molecular Chaperones; Protein Folding
PubMed: 23877967
DOI: 10.1002/bip.22361 -
International Journal of Molecular... Dec 2019Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco. These proteins' ability to prevent unwanted associations led to their being called... (Review)
Review
Thirty years ago a class of proteins was found to prevent the aggregation of Rubisco. These proteins' ability to prevent unwanted associations led to their being called chaperones. These chaperone proteins also increased in expression as a response to heat shock, hence their label as heat shock proteins (Hsps). However, neither label encompasses the breadth of these proteins' functional capabilities. The term "unfoldases" has been proposed, as this basic function is shared by most members of this protein family. Onto this is added specializations that allow the different family members to perform various cellular functions. This current article focuses on the resolved structural bases for these functions. It reviews the currently available molecular structures in the Protein Data Bank for several classes of Hsps (Hsp60, Hsp70, Hsp90, and Hsp104). When possible, it discusses the complete structures for these proteins, and the types of molecular machines to which they have been assigned. The structures of domains and the associated functions are discussed in order to illustrate the rationale for the proposed unfoldase function.
Topics: Bacteria; Databases, Protein; Eukaryota; History, 20th Century; History, 21st Century; Humans; Molecular Chaperones; Protein Conformation
PubMed: 31817979
DOI: 10.3390/ijms20246195 -
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 -
Journal of Structural Biology Oct 2006At the Cold Spring Harbor Meeting on 'Molecular Chaperones and the Heat Shock Response' in May 1996, Susan Lindquist presented evidence that a chaperone of yeast termed... (Review)
Review
At the Cold Spring Harbor Meeting on 'Molecular Chaperones and the Heat Shock Response' in May 1996, Susan Lindquist presented evidence that a chaperone of yeast termed Hsp104, which her group had been investigating for several years, is able to dissolve protein aggregates (Glover, J.R., Lindquist, S., 1998. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73-82). Among many of the participants this news stimulated reactions reaching from decided skepticism to utter disbelief because protein aggregation was widely considered to be an irreversible process. Several years and publications later, it is undeniable that Susan had been right. Hsp104 is an ATP dependent molecular machine that-in cooperation with Hsp70 and Hsp40-extracts polypeptide chains from protein aggregates and facilitates their refolding, although the molecular details of this process are still poorly understood. Meanwhile, close homologues of Hsp104 have been identified in bacteria (ClpB), in mitochondria (Hsp78), and in the cytosol of plants (Hsp101), but intriguingly not in the cytosol of animal cells (Mosser, D.D., Ho, S., Glover, J.R., 2004. Saccharomyces cerevisiae Hsp104 enhances the chaperone capacity of human cells and inhibits heat stress-induced proapoptotic signaling. Biochemistry 43, 8107-8115). Observations that Hsp104 plays an essential role in the maintenance of yeast prions (see review by James Shorter in this issue) have attracted even more attention to the molecular mechanism of this ATP dependent chaperone (Chernoff, Y.O., Lindquist, S.L., Ono, B., Inge-Vechtomov, S.G., Liebman, S.W., 1995. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [PSI+]. Science 268, 880-884).
Topics: Amino Acid Motifs; Amino Acid Sequence; Binding Sites; Conserved Sequence; Heat-Shock Proteins; Hydrolysis; Kinetics; Models, Biological; Models, Molecular; Molecular Chaperones; Molecular Sequence Data; Molecular Weight; Protein Binding; Protein Conformation; Protein Denaturation; Protein Structure, Tertiary; Substrate Specificity
PubMed: 16563798
DOI: 10.1016/j.jsb.2006.02.004