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FEBS Letters Jul 2023Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and... (Review)
Review
Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post-translational modifications and metabolite-based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.
Topics: Humans; Protein Folding; Molecular Chaperones; HSP90 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Processing, Post-Translational
PubMed: 37287189
DOI: 10.1002/1873-3468.14682 -
Medicinal Research Reviews Nov 2022The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic... (Review)
Review
The 94 kDa molecular chaperone, glucose-regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic reticulum (ER) stress and disease. Grp94 belongs to the Hsp90 family of molecular chaperones and is a master regulator of ER homeostasis due to its ability to fold and stabilize proteins/receptors, and to chaperone misfolded proteins for degradation. Multiple studies have demonstrated that Grp94 knockdown or inhibition leads to the degradation of client protein substrates, which leads to disruption of disease-dependent signaling pathways. As a result, small molecule inhibitors of Grp94 have become a promising therapeutic approach to target a variety of disease states. Specifically, Grp94 has proven to be a promising target for cancer, glaucoma, immune-mediated inflammation, and viral infection. Moreover, Grp94-peptide complexes have been utilized effectively as adjuvants for vaccines against a variety of disease states. This work highlights the significance of Grp94 biology and the development of therapeutics that target this molecular chaperone in multiple disease states.
Topics: Biology; HSP70 Heat-Shock Proteins; Humans; Membrane Glycoproteins; Membrane Proteins; Molecular Chaperones
PubMed: 35861260
DOI: 10.1002/med.21915 -
The Journal of Biological Chemistry Feb 2023An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular... (Review)
Review
An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular milieu face numerous challenges that can lead to protein misfolding and aggregation. As a checkpoint for proteins that move between cells, extracellular chaperone networks are of growing clinical relevance. J-domain proteins (JDPs) are ubiquitous molecular chaperones that are known for their essential roles in a wide array of fundamental cellular processes through their regulation of heat shock protein 70s. As the largest molecular chaperone family, JDPs have long been recognized for their diverse functions within cells. Some JDPs are elegantly selective for their "client proteins," some do not discriminate among substrates and others act cooperatively on the same target. The realization that JDPs are exported through both classical and unconventional secretory pathways has fueled investigation into the roles that JDPs play in protein quality control and intercellular communication. The proposed functions of exported JDPs are diverse. Studies suggest that export of DnaJB11 enhances extracellular proteostasis, that intercellular movement of DnaJB1 or DnaJB6 enhances the proteostasis capacity in recipient cells, whereas the import of DnaJB8 increases resistance to chemotherapy in recipient cancer cells. In addition, the export of DnaJC5 and concurrent DnaJC5-dependent ejection of dysfunctional and aggregation-prone proteins are implicated in the prevention of neurodegeneration. This review provides a brief overview of the current understanding of the extracellular chaperone networks and outlines the first wave of studies describing the cellular export of JDPs.
Topics: Humans; Molecular Chaperones; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Proteostasis; Nerve Tissue Proteins
PubMed: 36581212
DOI: 10.1016/j.jbc.2022.102840 -
Cell Stress & Chaperones Jul 2020Charcot-Marie-Tooth (CMT) disease is major hereditary neuropathy. CMT has been linked to mutations in a range of proteins, including the small heat shock protein HspB1.... (Review)
Review
Charcot-Marie-Tooth (CMT) disease is major hereditary neuropathy. CMT has been linked to mutations in a range of proteins, including the small heat shock protein HspB1. Here we review the properties of several HspB1 mutants associated with CMT. In vitro, mutations in the N-terminal domain lead to a formation of larger HspB1 oligomers when compared with the wild-type (WT) protein. These mutants are resistant to phosphorylation-induced dissociation and reveal lower chaperone-like activity than the WT on a range of model substrates. Mutations in the α-crystallin domain lead to the formation of yet larger HspB1 oligomers tending to dissociate at low protein concentration and having variable chaperone-like activity. Mutations in the conservative IPV motif within the C-terminal domain induce the formation of very large oligomers with low chaperone-like activity. Most mutants interact with a partner small heat shock protein, HspB6, in a manner different from that of the WT protein. The link between the altered physico-chemical properties and the pathological CMT phenotype is a subject of discussion. Certain HspB1 mutations appear to have an effect on cytoskeletal elements such as intermediate filaments and/or microtubules, and by this means damage the axonal transport. In addition, mutations of HspB1 can affect the metabolism in astroglia and indirectly modulate the viability of motor neurons. While the mechanisms of pathological mutations in HspB1 are likely to vary greatly across different mutations, further in vitro and in vivo studies are required for a better understanding of the CMT disease at molecular level.
Topics: Astrocytes; Charcot-Marie-Tooth Disease; HSP20 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Molecular Chaperones; Motor Neurons; Mutation; Protein Domains; Proteostasis
PubMed: 32301006
DOI: 10.1007/s12192-020-01099-9 -
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 -
Methods in Molecular Biology (Clifton,... 2023Extracellular heat shock proteins (HSP) play important roles in cell signaling and immunity. Many of these effects are mediated by surface receptors expressed on a wide...
Extracellular heat shock proteins (HSP) play important roles in cell signaling and immunity. Many of these effects are mediated by surface receptors expressed on a wide range of cell types, including immune cells. We have investigated the nature of such proteins by cloning candidate receptors into cells (CHO-K1) with the rare property of being null for HSP binding. Using this approach, we have discovered that mammalian and eukaryotic Hsp70 binds avidly to at least three classes of receptor including: (1) c-type lectin receptors (CLR), (2) scavenger receptors (SR) and (3) lectins. However, the structural nature of the receptor-ligand interactions is not currently clear. Hsp70 can bind to LOX-1 (a member of both the CLR and SR), with the c-type lectin binding domain (CTLD), to the SR family members SREC-I and FEEL-1/CLEVER-1/STABILIN-1, which by contrast have arrays of EGF-like repeats in their extracellular domains as well. In this chapter, we will discuss: (1) methods for the discovery of HSP receptors, (2) approaches to the study of individual receptors in cells that contain multiple such receptors and (3) methods for investigating HSP receptor function in vivo.
Topics: Animals; Molecular Chaperones; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Receptors, Scavenger; Lectins, C-Type; Mammals
PubMed: 37540436
DOI: 10.1007/978-1-0716-3342-7_15 -
Molecules (Basel, Switzerland) Jul 2020Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins,... (Review)
Review
Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.
Topics: Enzyme Activators; Enzyme Inhibitors; Humans; Molecular Chaperones; Mutation; Protein Folding
PubMed: 32660097
DOI: 10.3390/molecules25143145 -
Biochemical Pharmacology Jul 2022The molecular chaperone protein HSP60 is mainly distributed in mitochondria and assists protein folding under physiological and pathological conditions. Accumulating... (Review)
Review
The molecular chaperone protein HSP60 is mainly distributed in mitochondria and assists protein folding under physiological and pathological conditions. Accumulating evidence suggests abnormally expressed HSP60 in cancer is associated with clinicopathological features and prognosis of cancer patients. HSP60 could be used as a new biomarker for both diagnostic and prognostic purpose and tumor therapy. In this review article, we briefly described the structure, functional cycle, and regulatory mechanism of HSP60, and summarized its functional diversity in cancer as well as recent progress related to the diagnostic application of HSP60 and inhibitors against HSP60, which could provide us a comprehensive understanding about the value of HSP60 in tumor management.
Topics: Chaperonin 60; Humans; Mitochondria; Molecular Chaperones; Neoplasms; Protein Folding
PubMed: 35609646
DOI: 10.1016/j.bcp.2022.115096 -
Current Opinion in Structural Biology Feb 2020Designed ankyrin repeat proteins (DARPins) are artificial binding proteins that have found many uses in therapy, diagnostics and biochemical research. They substantially... (Review)
Review
Designed ankyrin repeat proteins (DARPins) are artificial binding proteins that have found many uses in therapy, diagnostics and biochemical research. They substantially extend the scope of antibody-derived binders. Their high affinity and specificity, rigidity, extended paratope, and facile bacterial production make them attractive for structural biology. Complexes with simple DARPins have been crystallized for a long time, but particularly the rigid helix fusion strategy has opened new opportunities. Rigid DARPin fusions expand crystallization space, enable recruitment of targets in a host lattice and reduce the size limit for cryo-EM. Besides applications in structural biology, rigid DARPin fusions also serve as molecular probes in cells to investigate spatial restraints in targets.
Topics: Animals; Ankyrin Repeat; Drug Design; Humans; Molecular Chaperones
PubMed: 31918361
DOI: 10.1016/j.sbi.2019.12.009 -
Molecular Biology Reports Jun 2022Heat shock proteins (HSPs) are stress-induced proteins that are important constituents of the cell's defense system. The activity of HSPs enhances when the cell... (Review)
Review
Heat shock proteins (HSPs) are stress-induced proteins that are important constituents of the cell's defense system. The activity of HSPs enhances when the cell undergoes undesirable environmental conditions like stress. The protective roles of HSPs are due to their molecular chaperone and anti-apoptotic functions. HSPs have a central role in the eye, and their malfunction has been associated with the manifestation of ocular diseases. Heat shock protein 27 (HSP27, HSPB1) is present in various ocular tissues, and it has been found to protect the eye from disease states such as retinoblastoma, uveal melanoma, glaucoma, and cataract. But some recent studies have shown the destructive role of HSP27 on retinal ganglionic cells. Thus, this article summarizes the role of heat shock protein 27 in eye and ocular diseases and will focus on the expression, regulation, and function of HSP27 in ocular complications.
Topics: HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Melanoma; Molecular Chaperones; Retinal Ganglion Cells; Uveal Neoplasms
PubMed: 35212927
DOI: 10.1007/s11033-022-07222-6