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Advances in Microbial Physiology 2001Protein folding in the cell, long thought to be a spontaneous process, in fact often requires the assistance of molecular chaperones. This is thought to be largely... (Review)
Review
Protein folding in the cell, long thought to be a spontaneous process, in fact often requires the assistance of molecular chaperones. This is thought to be largely because of the danger of incorrect folding and aggregation of proteins, which is a particular problem in the crowded environment of the cell. Molecular chaperones are involved in numerous processes in bacterial cells, including assisting the folding of newly synthesized proteins, both during and after translation; assisting in protein secretion, preventing aggregation of proteins on heat shock, and repairing proteins that have been damaged or misfolded by stresses such as a heat shock. Within the cell, a balance has to be found between refolding of proteins and their proteolytic degradation, and molecular chaperones play a key role in this. In this review, the evidence for the existence and role of the major cytoplasmic molecular chaperones will be discussed, mainly from the physiological point of view but also in relationship to their known structure, function and mechanism of action. The two major chaperone systems in bacterial cells (as typified by Escherichia coli) are the GroE and DnaK chaperones, and the contrasting roles and mechanisms of these chaperones will be presented. The GroE chaperone machine acts by providing a protected environment in which protein folding of individual protein molecules can proceed, whereas the DnaK chaperones act by binding and protecting exposed regions on unfolded or partially folded protein chains. DnaK chaperones interact with trigger factor in protein translation and with ClpB in reactivating proteins which have become aggregated after heat shock. The nature of the other cytoplasmic chaperones in the cell will also be reviewed, including those for which a clear function has not yet been determined, and those where an in vivo chaperone function has still to be proven, such as the small heat shock proteins IbpA and IbpB. The regulation of expression of the genes of the heat shock response will also be discussed, particularly in the light of the signals that are needed to induce the response. The major signals for induction of the heat shock response are elevated temperature and the presence of unfolded protein within the cell, but these are sensed and transduced differently by different bacteria. The best characterized example is the sigma 32 subunit of RNA polymerase from E. coli, which is both more efficiently translated and also transiently stabilized following heat shock. The DnaK chaperones modulate this effect. However, a more widely conserved system appears to be typified by the HrcA repressor in Bacillus subtilis, the activity of which is modulated by the GroE chaperone machine. Other examples of regulation of molecular chaperones will also be discussed. Finally, the likely future research directions for molecular chaperone biology in the post-genomic era will be briefly evaluated.
Topics: Bacillus subtilis; Bacterial Proteins; Chaperonins; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Molecular Chaperones; Protein Folding; Sigma Factor; Signal Transduction
PubMed: 11407116
DOI: 10.1016/s0065-2911(01)44012-4 -
Stem Cell Reports Jul 2023Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular...
Sarcomeres are fundamental to cardiac muscle contraction. Their impairment can elicit cardiomyopathies, leading causes of death worldwide. However, the molecular mechanism underlying sarcomere assembly remains obscure. We used human embryonic stem cell (hESC)-derived cardiomyocytes (CMs) to reveal stepwise spatiotemporal regulation of core cardiac myofibrillogenesis-associated proteins. We found that the molecular chaperone UNC45B is highly co-expressed with KINDLIN2 (KIND2), a marker of protocostameres, and later its distribution overlaps with that of muscle myosin MYH6. UNC45B-knockout CMs display essentially no contractility. Our phenotypic analyses further reveal that (1) binding of Z line anchor protein ACTN2 to protocostameres is perturbed because of impaired protocostamere formation, resulting in ACTN2 accumulation; (2) F-ACTIN polymerization is suppressed; and (3) MYH6 becomes degraded, so it cannot replace non-muscle myosin MYH10. Our mechanistic study demonstrates that UNC45B mediates protocostamere formation by regulating KIND2 expression. Thus, we show that UNC45B modulates cardiac myofibrillogenesis by interacting spatiotemporally with various proteins.
Topics: Humans; Molecular Chaperones; Muscle Development; Myocytes, Cardiac; Myosins; Sarcomeres
PubMed: 37295424
DOI: 10.1016/j.stemcr.2023.05.006 -
European Journal of Medicinal Chemistry Dec 2023Abnormal post-translational modification of microtubule-associated protein Tau (MAPT) is a prominent pathological feature in Alzheimer's disease (AD). Previous research... (Review)
Review
Abnormal post-translational modification of microtubule-associated protein Tau (MAPT) is a prominent pathological feature in Alzheimer's disease (AD). Previous research has focused on designing small molecules to target Tau modification, aiming to restore microtubule stability and regulate Tau levels in vivo. However, progress has been hindered, and no effective Tau-targeted drugs have been successfully marketed, which urgently requires more strategies. Heat shock proteins (HSPs), especially Hsp90 and Hsp70, have been found to play a crucial role in Tau maturation and degradation. This review explores innovative approaches using small molecules that interact with the chaperone system to regulate Tau levels. We provide a comprehensive overview of the mechanisms involving HSPs and their co-chaperones in the Tau regulation cycle. Additionally, we analyze small molecules targeting these chaperone systems to modulate Tau function. By understanding the characteristics of the molecular chaperone system and its specific impact on Tau, we aim to provide a perspective that seeks to regulate Tau levels through the manipulation of the molecular chaperone system and ultimately develop effective treatments for AD.
Topics: Humans; tau Proteins; Molecular Chaperones; Alzheimer Disease; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; HSP70 Heat-Shock Proteins
PubMed: 37839344
DOI: 10.1016/j.ejmech.2023.115859 -
Annual Review of Biochemistry 2006Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell. Biochemical and structural analysis of... (Review)
Review
Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell. Biochemical and structural analysis of Hsp90 has revealed a complex mechanism of ATPase-coupled conformational changes and interactions with cochaperone proteins, which facilitate activation of Hsp90's diverse "clientele." Despite recent progress, key aspects of the ATPase-coupled mechanism of Hsp90 remain controversial, and the nature of the changes, engendered by Hsp90 in client proteins, is largely unknown. Here, we discuss present knowledge of Hsp90 structure and function gleaned from crystallographic studies of individual domains and recent progress in obtaining a structure for the ATP-bound conformation of the intact dimeric chaperone. Additionally, we describe the roles of the plethora of cochaperones with which Hsp90 cooperates and growing insights into their biochemical mechanisms, which come from crystal structures of Hsp90 cochaperone complexes.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Binding Sites; Dimerization; Enzyme Activation; Fungal Proteins; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Chaperones; Multiprotein Complexes; Protein Structure, Quaternary; Protein Structure, Tertiary
PubMed: 16756493
DOI: 10.1146/annurev.biochem.75.103004.142738 -
Cell Structure and Function Oct 1996
Review
Topics: Animals; Collagen; Gene Expression Regulation; Heat-Shock Proteins; Liver Cirrhosis; Molecular Chaperones; Procollagen
PubMed: 9118251
DOI: 10.1247/csf.21.425 -
Neurotherapeutics : the Journal of the... Jul 2013A common pathological hallmark of protein-conformational brain diseases is the formation of disease-specific protein aggregates. In Alzheimer's disease, these are... (Review)
Review
A common pathological hallmark of protein-conformational brain diseases is the formation of disease-specific protein aggregates. In Alzheimer's disease, these are comprised of amyloid-β and Tau as opposed to α-synuclein in Parkinson's disease and N-terminal fragments of mutant huntingtin in Huntington's disease. Most aggregates also sequester molecular chaperones, a protein family that assists in the folding, refolding, stabilization, and processing of client proteins, including misfolded proteins in brain diseases. Molecular chaperone modulation has achieved remarkable therapeutic effects in some cellular and preclinical animal models of protein-conformational diseases. This has raised hope for chaperone-based strategies to combat these diseases. Here, we review briefly the functional diversity and medical significance of molecular chaperones, their therapeutic potential, and common and specific challenges towards clinical application.
Topics: Animals; Brain; Humans; Molecular Chaperones; Proteostasis Deficiencies
PubMed: 23536253
DOI: 10.1007/s13311-013-0186-5 -
Genetics Aug 1999A major finding within the field of archaea and molecular chaperones has been the demonstration that, while some species have the stress (heat-shock) gene hsp70(dnaK),... (Comparative Study)
Comparative Study Review
A major finding within the field of archaea and molecular chaperones has been the demonstration that, while some species have the stress (heat-shock) gene hsp70(dnaK), others do not. This gene encodes Hsp70(DnaK), an essential molecular chaperone in bacteria and eukaryotes. Due to the physiological importance and the high degree of conservation of this protein, its absence in archaeal organisms has raised intriguing questions pertaining to the evolution of the chaperone machine as a whole and that of its components in particular, namely, Hsp70(DnaK), Hsp40(DnaJ), and GrpE. Another archaeal paradox is that the proteins coded by these genes are very similar to bacterial homologs, as if the genes had been received via lateral transfer from bacteria, whereas the upstream flanking regions have no bacterial markers, but instead have typical archaeal promoters, which are like those of eukaryotes. Furthermore, the chaperonin system in all archaea studied to the present, including those that possess a bacterial-like chaperone machine, is similar to that of the eukaryotic-cell cytosol. Thus, two chaperoning systems that are designed to interact with a compatible partner, e.g., the bacterial chaperone machine physiologically interacts with the bacterial but not with the eucaryal chaperonins, coexist in archaeal cells in spite of their apparent functional incompatibility. It is difficult to understand how these hybrid characteristics of the archaeal chaperoning system became established and work, if one bears in mind the classical ideas learned from studying bacteria and eukaryotes. No doubt, archaea are intriguing organisms that offer an opportunity to find novel molecules and mechanisms that will, most likely, enhance our understanding of the stress response and the protein folding and refolding processes in the three phylogenetic domains.
Topics: Archaea; Archaeal Proteins; Bacterial Proteins; Escherichia coli Proteins; Evolution, Molecular; Genes, Archaeal; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Macromolecular Substances; Molecular Chaperones; Protein Conformation; Protein Folding
PubMed: 10430558
DOI: 10.1093/genetics/152.4.1277 -
The Biochemical Journal Feb 2020Deficits in protein homeostasis (proteostasis) are typified by the partial unfolding or misfolding of native proteins leading to amorphous or fibrillar aggregation,...
Deficits in protein homeostasis (proteostasis) are typified by the partial unfolding or misfolding of native proteins leading to amorphous or fibrillar aggregation, events that have been closely associated with diseases including Alzheimer's and Parkinson's diseases. Molecular chaperones are intimately involved in maintaining proteostasis, and their mechanisms of action are in part dependent on the morphology of aggregation-prone proteins. This study utilised native ion mobility-mass spectrometry to provide molecular insights into the conformational properties and dynamics of a model protein, α-lactalbumin (α-LA), which aggregates in an amorphous or amyloid fibrillar manner controlled by appropriate selection of experimental conditions. The molecular chaperone β-casein (β-CN) is effective at inhibiting amorphous and fibrillar aggregation of α-LA at sub-stoichiometric ratios, with greater efficiency against fibril formation. Analytical size-exclusion chromatography demonstrates the interaction between β-CN and amorphously aggregating α-LA is stable, forming a soluble high molecular weight complex, whilst with fibril-forming α-LA the interaction is transient. Moreover, ion mobility-mass spectrometry (IM-MS) coupled with collision-induced unfolding (CIU) revealed that α-LA monomers undergo distinct conformational transitions during the initial stages of amorphous (order to disorder) and fibrillar (disorder to order) aggregation. The structural heterogeneity of monomeric α-LA during fibrillation is reduced in the presence of β-CN along with an enhancement in stability, which provides a potential means for preventing fibril formation. Together, this study demonstrates how IM-MS and CIU can investigate the unfolding of proteins as well as examine transient and dynamic protein-chaperone interactions, and thereby provides detailed insight into the mechanism of chaperone action and proteostasis mechanisms.
Topics: Amyloid; Caseins; Lactalbumin; Mass Spectrometry; Molecular Chaperones; Protein Aggregates; Protein Folding; Proteostasis
PubMed: 31939601
DOI: 10.1042/BCJ20190638 -
Advances in Protein Chemistry 2001
Review
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Binding
PubMed: 11868271
DOI: 10.1016/s0065-3233(01)59005-1 -
Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain.Protein Science : a Publication of the... Jul 2024Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone...
Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein. High-confidence AlphaFold2 and RoseTTAFold predictions suggest that the intramolecular amyloidogenic region (Bri23) is part of the hydrophobic core of the proprotein, where it occupies the proposed amyloid binding site, explaining the markedly reduced ability of the proprotein to prevent an exogenous amyloidogenic peptide from aggregating. However, the BRICHOS-Bri23 complex maintains its ability to form large polydisperse oligomers that prevent amorphous protein aggregation. A cryo-EM-derived model of the Bri2 BRICHOS oligomer is compatible with surface-exposed hydrophobic motifs that get exposed and come together during oligomerization, explaining its effects against amorphous aggregation. These findings provide a molecular basis for the BRICHOS chaperone domain function, where distinct surfaces are employed against different forms of protein aggregation.
Topics: Molecular Chaperones; Binding Sites; Humans; Protein Domains; Adaptor Proteins, Signal Transducing; Models, Molecular; Hydrophobic and Hydrophilic Interactions
PubMed: 38864729
DOI: 10.1002/pro.5063