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Biochimica Et Biophysica Acta Aug 2014Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as... (Review)
Review
Nascent polypeptides emerging from the ribosome are assisted by a pool of molecular chaperones and targeting factors, which enable them to efficiently partition as cytosolic, integral membrane or exported proteins. Extensive genetic and biochemical analyses have significantly expanded our knowledge of chaperone tasking throughout this process. In bacteria, it is known that the folding of newly-synthesized cytosolic proteins is mainly orchestrated by three highly conserved molecular chaperones, namely Trigger Factor (TF), DnaK (HSP70) and GroEL (HSP60). Yet, it has been reported that these major chaperones are strongly involved in protein translocation pathways as well. This review describes such essential molecular chaperone functions, with emphasis on both the biogenesis of inner membrane proteins and the post-translational targeting of presecretory proteins to the Sec and the twin-arginine translocation (Tat) pathways. Critical interplay between TF, DnaK, GroEL and other molecular chaperones and targeting factors, including SecB, SecA, the signal recognition particle (SRP) and the redox enzyme maturation proteins (REMPs) is also discussed. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Bacteria; Cell Membrane; Chaperonin 60; HSP70 Heat-Shock Proteins; Molecular Chaperones; Oxidation-Reduction; Protein Transport; Signal Recognition Particle
PubMed: 24269840
DOI: 10.1016/j.bbamcr.2013.11.007 -
Seminars in Cancer Biology Nov 2021TRAP1, the mitochondrial component of the Hsp90 family of molecular chaperones, displays important bioenergetic and proteostatic functions. In tumor cells, TRAP1... (Review)
Review
TRAP1, the mitochondrial component of the Hsp90 family of molecular chaperones, displays important bioenergetic and proteostatic functions. In tumor cells, TRAP1 contributes to shape metabolism, dynamically tuning it with the changing environmental conditions, and to shield from noxious insults. Hence, TRAP1 activity has profound effects on the capability of neoplastic cells to evolve towards more malignant phenotypes. Here, we discuss our knowledge on the biochemical functions of TRAP1 in the context of a growing tumor mass, and we analyze the possibility of targeting its chaperone functions for developing novel anti-neoplastic approaches.
Topics: Animals; HSP90 Heat-Shock Proteins; Humans; Neoplasms
PubMed: 34242740
DOI: 10.1016/j.semcancer.2021.07.002 -
JCI Insight Mar 2022Molecular chaperones are responsible for maintaining cellular homeostasis, and one such chaperone, GRP170, is an endoplasmic reticulum (ER) resident that oversees both...
Molecular chaperones are responsible for maintaining cellular homeostasis, and one such chaperone, GRP170, is an endoplasmic reticulum (ER) resident that oversees both protein biogenesis and quality control. We previously discovered that GRP170 regulates the degradation and assembly of the epithelial sodium channel (ENaC), which reabsorbs sodium in the distal nephron and thereby regulates salt-water homeostasis and blood pressure. To define the role of GRP170 - and, more generally, molecular chaperones in kidney physiology - we developed an inducible, nephron-specific GRP170-KO mouse. Here, we show that GRP170 deficiency causes a dramatic phenotype: profound hypovolemia, hyperaldosteronemia, and dysregulation of ion homeostasis, all of which are associated with the loss of ENaC. Additionally, the GRP170-KO mouse exhibits hallmarks of acute kidney injury (AKI). We further demonstrate that the unfolded protein response (UPR) is activated in the GRP170-deficient mouse. Notably, the UPR is also activated in AKI when originating from various other etiologies, including ischemia, sepsis, glomerulonephritis, nephrotic syndrome, and transplant rejection. Our work establishes the central role of GRP170 in kidney homeostasis and directly links molecular chaperone function to kidney injury.
Topics: Acute Kidney Injury; Animals; Endoplasmic Reticulum Stress; HSP70 Heat-Shock Proteins; Mice; Molecular Chaperones
PubMed: 35104250
DOI: 10.1172/jci.insight.151869 -
Nature Communications Jan 2023The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation...
The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease.
Topics: Humans; DNA-Binding Proteins; Heat-Shock Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Molecular Chaperones; Prions; Protein Aggregates
PubMed: 36709343
DOI: 10.1038/s41467-023-36023-z -
FEBS Letters Dec 2018Iron-sulfur cluster biogenesis is a complex process mediated by numerous proteins among which two from bacteria chaperones, called HscB and HscA in bacteria. They are... (Review)
Review
Iron-sulfur cluster biogenesis is a complex process mediated by numerous proteins among which two from bacteria chaperones, called HscB and HscA in bacteria. They are highly conserved up to eukaryotes and homologous to DnaJ and DnaK, respectively, but with specific differences. As compared with other chaperones, HscB and HscA have escaped attention and relatively little is known about their functions. After briefly introducing the various chaperone families, we reviewed here the current structural and functional knowledge HscA and HscB and on their role in cluster formation. We critically evaluated the literature and highlighted the weak aspects which will require more attention in the future. We sincerely hope that this study will inspire new interest on this important and interesting system.
Topics: Bacterial Proteins; Escherichia coli; Escherichia coli Proteins; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Iron-Sulfur Proteins; Models, Molecular; Molecular Chaperones; Multigene Family; Protein Domains
PubMed: 30194723
DOI: 10.1002/1873-3468.13245 -
International Journal of Molecular... Feb 2024Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is... (Review)
Review
Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in , the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.
Topics: Humans; Desmin; Cardiomyopathies; Mutation; Cardiomyopathy, Restrictive; Molecular Chaperones
PubMed: 38474073
DOI: 10.3390/ijms25052826 -
Science Advances Dec 2022The ability of heat shock protein 70 (Hsp70) molecular chaperones to remodel the conformation of their clients is central to their biological function; however,...
The ability of heat shock protein 70 (Hsp70) molecular chaperones to remodel the conformation of their clients is central to their biological function; however, questions remain regarding the precise molecular mechanisms by which Hsp70 machinery interacts with the client and how this contributes toward efficient protein folding. Here, we used total internal reflection fluorescence (TIRF) microscopy and single-molecule fluorescence resonance energy transfer (smFRET) to temporally observe the conformational changes that occur to individual firefly luciferase proteins as they are folded by the bacterial Hsp70 system. We observed multiple cycles of chaperone binding and release to an individual client during refolding and determined that high rates of chaperone cycling improves refolding yield. Furthermore, we demonstrate that DnaJ remodels misfolded proteins via a conformational selection mechanism, whereas DnaK resolves misfolded states via mechanical unfolding. This study illustrates that the temporal observation of chaperone-assisted folding enables the elucidation of key mechanistic details inaccessible using other approaches.
Topics: Humans; Escherichia coli Proteins; Heat-Shock Proteins; Escherichia coli; Protein Folding; Molecular Chaperones; HSP70 Heat-Shock Proteins
PubMed: 36516244
DOI: 10.1126/sciadv.add0922 -
International Journal of Molecular... Jul 2019The recruitment and transference of proteins through protein-protein interactions is a general process involved in various biological functions in cells. Despite the...
The recruitment and transference of proteins through protein-protein interactions is a general process involved in various biological functions in cells. Despite the importance of this general process, the dynamic mechanism of how proteins are recruited and transferred from one interacting partner to another remains unclear. In this study, we investigated the dynamic mechanisms of recruitment and translocation of histone chaperone CIA/ASF1 for nucleosome disassembly by exploring the conformational space and the free energy profile of unbound DBD(CCG1) and CIA/ASF1-bound DBD(CCG1) systems through extensive molecular dynamics simulations. It was found that there exists three metastable conformational states for DBD(CCG1), an unbound closed state, a CIA/ASF1-bound half-open state, and an open state. The free energy landscape shows that the closed state and the half-open state are separated by a high free energy barrier, while the half-open state and the open state are connected with a moderate free energy increase. The high free energy barrier between the closed and half-open states explains why DBD(CCG1) can recruit CIA/ASF1 and remain in the binding state during the transportation. In addition, the asymmetric binding of CIA/ASF1 on DBD(CCG1) allows DBD(CCG1) to adopt the open state by moving one of its two domains, such that the exposed domain of DBD(CCG1) is able to recognize the acetylated histone H4 tails. As such, CIA/ASF1 has a chance to translocate from DBD(CCG1) to histone, which is also facilitated by the moderate energy increase from the bound half-open state to the open state of DBD(CCG1). These findings suggest that the recruitment and transference of histone chaperone CIA/ASF1 is highly favored by its interaction with DBD(CCG1) via conformational selection and asymmetric binding, which may represent a general mechanism of similar biological processes.
Topics: Cell Cycle Proteins; Histone Chaperones; Hydrogen Bonding; Models, Molecular; Molecular Chaperones; Mutation; Protein Binding; Protein Conformation; Protein Stability; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Thermodynamics
PubMed: 31284555
DOI: 10.3390/ijms20133325 -
Cell Stress & Chaperones Sep 2023Chaperone proteins have crucial roles to play in all animal species and are involved in mediating both the folding of newly synthesized peptides into their mature... (Review)
Review
Chaperone proteins have crucial roles to play in all animal species and are involved in mediating both the folding of newly synthesized peptides into their mature conformation, the refolding of misfolded proteins, and the trafficking of proteins between subcellular compartments. These highly conserved proteins have particularly important roles to play in dealing with disruptions of the proteome as a result of environmental stress since abiotic factors, including temperature, pressure, oxygen, water availability, and pollutants can readily disrupt the conformation and/or function of all types of proteins, e.g., enzymes, transporters, and structural proteins. The current review provides an update on recent advances in understanding the roles and responses of chaperones in aiding animals to deal with environmental stress, offering new information on chaperone action in supporting survival strategies including torpor, hibernation, anaerobiosis, estivation, and cold/freeze tolerance among both vertebrate and invertebrate species.
Topics: Animals; Heat-Shock Proteins; Molecular Chaperones; Protein Folding; Cold Temperature; Temperature
PubMed: 36441380
DOI: 10.1007/s12192-022-01312-x -
Protein Science : a Publication of the... Mar 2016Although chaperone-assisted protein crystallization remains a comparatively rare undertaking, the number of crystal structures of polypeptides fused to maltose-binding... (Review)
Review
Although chaperone-assisted protein crystallization remains a comparatively rare undertaking, the number of crystal structures of polypeptides fused to maltose-binding protein (MBP) that have been deposited in the Protein Data Bank (PDB) has grown dramatically during the past decade. Altogether, 102 fusion protein structures were detected by Basic Local Alignment Search Tool (BLAST) analysis. Collectively, these structures comprise a range of sizes, space groups, and resolutions that are typical of the PDB as a whole. While most of these MBP fusion proteins were equipped with short inter-domain linkers to increase their rigidity, fusion proteins with long linkers have also been crystallized. In some cases, surface entropy reduction mutations in MBP appear to have facilitated the formation of crystals. A comparison of the structures of fused and unfused proteins, where both are available, reveals that MBP-mediated structural distortions are very rare.
Topics: Amino Acid Sequence; Animals; Cloning, Molecular; Crystallization; Crystallography; Entropy; Humans; Maltose-Binding Proteins; Models, Molecular; Molecular Chaperones; Mutation; Peptides; Protein Conformation; Recombinant Fusion Proteins
PubMed: 26682969
DOI: 10.1002/pro.2863