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Cancers Feb 2024Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of... (Review)
Review
Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions.
PubMed: 38339390
DOI: 10.3390/cancers16030638 -
Current Opinion in Structural Biology Jun 2024Proteome complexity has expanded tremendously over evolutionary time, enabling biological diversification. Much of this complexity is achieved by combining a limited set... (Review)
Review
Proteome complexity has expanded tremendously over evolutionary time, enabling biological diversification. Much of this complexity is achieved by combining a limited set of structural units into long polypeptides. This widely used evolutionary strategy poses challenges for folding of the resulting multi-domain proteins. As a consequence, their folding differs from that of small single-domain proteins, which generally fold quickly and reversibly. Co-translational processes and chaperone interactions are important aspects of multi-domain protein folding. In this review, we discuss some of the recent experimental progress toward understanding these processes.
Topics: Protein Folding; Protein Domains; Proteins; Molecular Chaperones; Humans; Models, Molecular; Animals
PubMed: 38432063
DOI: 10.1016/j.sbi.2024.102790 -
Biomolecules Aug 2023The treatment landscape for lysosomal storage disorders (LSDs) is rapidly evolving. An increase in the number of preclinical and clinical studies in the last decade has... (Review)
Review
The treatment landscape for lysosomal storage disorders (LSDs) is rapidly evolving. An increase in the number of preclinical and clinical studies in the last decade has demonstrated that pharmacological chaperones are a feasible alternative to enzyme replacement therapy (ERT) for individuals with LSDs. A systematic search was performed to retrieve and critically assess the evidence from preclinical and clinical applications of pharmacological chaperones in the treatment of LSDs and to elucidate the mechanisms by which they could be effective in clinical practice. Publications were screened according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. Fifty-two articles evaluating 12 small molecules for the treatment of seven LSDs are included in this review. Overall, a substantial amount of preclinical and clinical data support the potential of pharmacological chaperones as treatments for Fabry disease, Gaucher disease, and Pompe disease. Most of the available clinical evidence evaluated migalastat for the treatment of Fabry disease. There was a lack of consistency in the terminology used to describe pharmacological chaperones in the literature. Therefore, the new small molecule chaperone (SMC) classification system is proposed to inform a standardized approach for new, emerging small molecule therapies in LSDs.
Topics: Humans; Lysosomal Storage Diseases; Fabry Disease; Gaucher Disease; Enzyme Replacement Therapy; Lysosomes
PubMed: 37627292
DOI: 10.3390/biom13081227 -
The Journal of Clinical Investigation Oct 2023Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine...
Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).
Topics: Humans; Cystinosis; Cystine; Endoplasmic Reticulum-Associated Degradation; Precision Medicine; Mutation; Molecular Chaperones; Lysosomes
PubMed: 37561577
DOI: 10.1172/JCI169551 -
Cells Feb 2024The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated... (Review)
Review
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction-cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed.
Topics: Animals; Cytoskeleton; Intercellular Junctions; Actin Cytoskeleton; Actomyosin; Molecular Chaperones; Mammals
PubMed: 38474334
DOI: 10.3390/cells13050370 -
Cell Reports Oct 2023All vertebrate genomes encode for three large histone H2A variants that have an additional metabolite-binding globular macrodomain module, macroH2A. MacroH2A variants...
All vertebrate genomes encode for three large histone H2A variants that have an additional metabolite-binding globular macrodomain module, macroH2A. MacroH2A variants impact heterochromatin organization and transcription regulation and establish a barrier for cellular reprogramming. However, the mechanisms of how macroH2A is incorporated into chromatin and the identity of any chaperones required for histone deposition remain elusive. Here, we develop a split-GFP-based assay for chromatin incorporation and use it to conduct a genome-wide mutagenesis screen in haploid human cells to identify proteins that regulate macroH2A dynamics. We show that the histone chaperone ANP32B is a regulator of macroH2A deposition. ANP32B associates with macroH2A in cells and in vitro binds to histones with low nanomolar affinity. In vitro nucleosome assembly assays show that ANP32B stimulates deposition of macroH2A-H2B and not of H2A-H2B onto tetrasomes. In cells, depletion of ANP32B strongly affects global macroH2A chromatin incorporation, revealing ANP32B as a macroH2A histone chaperone.
Topics: Humans; Histones; Chromatin; Histone Chaperones; Gene Expression Regulation; Molecular Chaperones; Nucleosomes; Nuclear Proteins
PubMed: 37858472
DOI: 10.1016/j.celrep.2023.113300 -
International Journal of Molecular... May 2024Molecular chaperones are highly conserved across evolution and play a crucial role in preserving protein homeostasis. The 60 kDa heat shock protein (HSP60), also... (Review)
Review
Molecular chaperones are highly conserved across evolution and play a crucial role in preserving protein homeostasis. The 60 kDa heat shock protein (HSP60), also referred to as chaperonin 60 (Cpn60), resides within mitochondria and is involved in maintaining the organelle's proteome integrity and homeostasis. The HSP60 family, encompassing Cpn60, plays diverse roles in cellular processes, including protein folding, cell signaling, and managing high-temperature stress. In prokaryotes, HSP60 is well understood as a GroEL/GroES complex, which forms a double-ring cavity and aids in protein folding. In eukaryotes, HSP60 is implicated in numerous biological functions, like facilitating the folding of native proteins and influencing disease and development processes. Notably, research highlights its critical involvement in sustaining oxidative stress and preserving mitochondrial integrity. HSP60 perturbation results in the loss of the mitochondria integrity and activates apoptosis. Currently, numerous clinical investigations are in progress to explore targeting HSP60 both in vivo and in vitro across various disease models. These studies aim to enhance our comprehension of disease mechanisms and potentially harness HSP60 as a therapeutic target for various conditions, including cancer, inflammatory disorders, and neurodegenerative diseases. This review delves into the diverse functions of HSP60 in regulating proteo-homeostasis, oxidative stress, ROS, apoptosis, and its implications in diseases like cancer and neurodegeneration.
Topics: Chaperonin 60; Humans; Animals; Oxidative Stress; Mitochondria; Neoplasms; Apoptosis; Neurodegenerative Diseases; Protein Folding; Reactive Oxygen Species
PubMed: 38791521
DOI: 10.3390/ijms25105483 -
Molecules (Basel, Switzerland) Aug 2023The creation of new proteins by combining natural domains is a commonly used technique in protein engineering. In this work, we have tested the possibilities and...
The creation of new proteins by combining natural domains is a commonly used technique in protein engineering. In this work, we have tested the possibilities and limitations of using circular homo-oligomeric Sm-like proteins as a basis for attaching other domains. Attachment to such a stable base should bring target domains together and keep them in the correct mutual orientation. We chose a circular homoheptameric Sm-like protein from as a stable backbone and the apical domain of the GroEL chaperone protein as the domain of study. This domain by itself, separated from the rest of the GroEL molecule, does not form an oligomeric ring. In our design, the hyperstable SacSm held the seven ADGroELs together and forced them to oligomerize. The designed hybrid protein was obtained and studied with various physical and chemical methods. Stepwise assembly and self-organization of this protein have been shown. First, the SacSm base was assembled, and then ADGroEL was folded on it. Functional testing showed that the obtained fusion protein was able to bind the same non-native proteins as the full-length GroEL chaperone. It also reduced the aggregation of a number of proteins when they were heated, which confirms its chaperone activity. Thus, the engineering path we chose made it possible to create an efficient thermostable chaperone. The result obtained shows the productivity of the way we chose for the creation and stabilization of oligomeric proteins.
Topics: Molecular Chaperones; Protein Folding; Chaperonin 60; Engineering; Hot Temperature
PubMed: 37687025
DOI: 10.3390/molecules28176196 -
Advanced Science (Weinheim,... May 2024Epigenetic modifiers that accumulate in oocytes, play a crucial role in steering the developmental program of cleavage embryos and initiating life. However, the...
Epigenetic modifiers that accumulate in oocytes, play a crucial role in steering the developmental program of cleavage embryos and initiating life. However, the identification of key maternal epigenetic regulators remains elusive. In the findings, the essential role of maternal Ep400, a chaperone for H3.3, in oocyte quality and early embryo development in mice is highlighted. Depletion of Ep400 in oocytes resulted in a decline in oocyte quality and abnormalities in fertilization. Preimplantation embryos lacking maternal Ep400 exhibited reduced major zygotic genome activation (ZGA) and experienced developmental arrest at the 2-to-4-cell stage. The study shows that EP400 forms protein complex with NFYA, occupies promoters of major ZGA genes, modulates H3.3 distribution between euchromatin and heterochromatin, promotes transcription elongation, activates the expression of genes regulating mitochondrial functions, and facilitates the expression of rate-limiting enzymes of the TCA cycle. This intricate process driven by Ep400 ensures the proper execution of the developmental program, emphasizing its critical role in maternal-to-embryonic transition.
Topics: Animals; Mice; Oocytes; Zygote; Female; Embryonic Development; Chromatin; Gene Expression Regulation, Developmental; Molecular Chaperones; Epigenesis, Genetic; E1A-Associated p300 Protein
PubMed: 38493496
DOI: 10.1002/advs.202308018 -
PloS One 2023The coding and promoter region sequences from the BiP-like protein SBiP1 from Symbiodinium microadriaticum CassKB8 were obtained by PCR, sequenced and compared with...
The coding and promoter region sequences from the BiP-like protein SBiP1 from Symbiodinium microadriaticum CassKB8 were obtained by PCR, sequenced and compared with annotated sequences. The nucleotides corresponding to the full sequence were correctly annotated and the main SBiP1 features determined at the nucleotide and amino acid level. The translated protein was organized into the typical domains of the BiP/HSP70 family including a signal peptide, a substrate- and a nucleotide-binding domain, and an ER localization sequence. Conserved motifs included a highly conserved Thr513 phosphorylation site and two ADP-ribosylation sites from eukaryotic BiP's. Molecular modeling showed the corresponding domain regions and main exposed post-translational target sites in its three-dimensional structure, which also closely matched Homo sapiens BiP further indicating that it indeed corresponds to a BiP/HSP70 family protein. The gene promoter region showed at least eight light regulation-related sequences consistent with the molecule being highly phosphorylated in Thr under dark conditions and dephosphorylated upon light stimuli. We tested light parameter variations that could modulate the light mediated phosphorylation effect and found that SBiP1 Thr dephosphorylation was only significantly detected after 15-30 min light stimulation. Such light-induced dephosphorylation was observed even when dichlorophenyl dimethyl urea, a photosynthesis inhibitor, was also present in the cells during the light stimulation. Dephosphorylation occurred indistinctly under red, yellow, blue or the full visible light spectra. In additon, it was observed at a light intensity of as low as 1 μmole photon m-2 s-1. Our results indicate that: a) SBiP1 is a chaperone belonging to the BiP/HSP70 family proteins; b) its light-modulated phosphorylation/dephosphorylation most likely functions as an activity switch for the chaperone; c) this light-induced modulation occurs relatively slow but is highly sensitive to the full spectrum of visible light; and d) the light induced Thr dephosphorylation is independent of photosynthetic activity in these cells.
Topics: Humans; Phosphorylation; Protein Binding; Molecular Chaperones; HSP70 Heat-Shock Proteins; Endoplasmic Reticulum Chaperone BiP; Nucleotides
PubMed: 37862348
DOI: 10.1371/journal.pone.0293299