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Journal of Molecular Biology Apr 2020Small heat-shock proteins (sHSPs) are molecular chaperones that respond to cellular stresses to combat protein aggregation. HSP27 is a critical human sHSP that forms...
Small heat-shock proteins (sHSPs) are molecular chaperones that respond to cellular stresses to combat protein aggregation. HSP27 is a critical human sHSP that forms large, dynamic oligomers whose quaternary structures and chaperone activities depend on environmental factors. Upon exposure to cellular stresses, such as heat shock or acidosis, HSP27 oligomers can dissociate into dimers and monomers, which leads to significantly enhanced chaperone activity. The structured core of the protein, the α-crystallin domain (ACD), forms dimers and can prevent the aggregation of substrate proteins to a similar degree as the full-length protein. When the ACD dimer dissociates into monomers, it partially unfolds and exhibits enhanced activity. Here, we used solution-state NMR spectroscopy to characterize the structure and dynamics of the HSP27 ACD monomer. Web show that the monomer is stabilized at low pH and that its backbone chemical shifts, N relaxation rates, and H-N residual dipolar couplings suggest structural changes and rapid motions in the region responsible for dimerization. By analyzing the solvent accessible and buried surface areas of sHSP structures in the context of a database of dimers that are known to dissociate into disordered monomers, we predict that ACD dimers from sHSPs across all kingdoms of life may partially unfold upon dissociation. We propose a general model in which conditional disorder-the partial unfolding of ACDs upon monomerization-is a common mechanism for sHSP activity.
Topics: Heat-Shock Proteins; Humans; Hydrogen-Ion Concentration; Models, Molecular; Molecular Chaperones; Protein Binding; Protein Folding; Protein Multimerization; Protein Structure, Quaternary; Protein Unfolding
PubMed: 32081587
DOI: 10.1016/j.jmb.2020.02.003 -
Free Radical Biology & Medicine Aug 2020Large-size subunit catalases (LSCs) have a C-terminal domain that is structurally similar to DJ-1 and Hsp31 proteins, which have well documented molecular chaperone...
Large-size subunit catalases (LSCs) have a C-terminal domain that is structurally similar to DJ-1 and Hsp31 proteins, which have well documented molecular chaperone activity. Like chaperones, LSCs are abundant proteins that are induced under stress conditions and during cell differentiation in different microorganisms. Here we document that the C-terminal domain of LSCs assist other proteins to preserve their active conformation. Heat, urea, or HO denaturation of alcohol dehydrogenase was prevented by LSCs or the C-terminal domain of Catalase-3 (TDC3); in contrast, small-size subunit catalases (SSCs) or LSCs without the C-terminal domain (C3 or C63) did not have this effect. Similar results were obtained if the alcohol dehydrogenase was previously denatured by heat and then the different catalases or truncated enzymes were added. The TDC3 also protected both the C3 and the bovine liver catalase from heat denaturation. The chaperone activity of CAT-3 or the TDC3 increased survival of E. coli under different stress conditions whereas the C3 did not. It is concluded that the C-terminal domain of LSCs has a chaperone activity that is instrumental for cellular resistance to stress conditions, such as oxidative stress that leads to cell differentiation in filamentous fungi.
Topics: Animals; Catalase; Cattle; Escherichia coli; Hydrogen Peroxide; Molecular Chaperones; Protein Folding
PubMed: 32502516
DOI: 10.1016/j.freeradbiomed.2020.05.020 -
Cell Stress & Chaperones Nov 2023Epilepsy is a group of neurological diseases which requires significant economic costs for the treatment and care of patients. The central point of epileptogenesis stems... (Review)
Review
Epilepsy is a group of neurological diseases which requires significant economic costs for the treatment and care of patients. The central point of epileptogenesis stems from the failure of synaptic signal transmission mechanisms, leading to excessive synchronous excitation of neurons and characteristic epileptic electroencephalogram activity, in typical cases being manifested as seizures and loss of consciousness. The causes of epilepsy are extremely diverse, which is one of the reasons for the complexity of selecting a treatment regimen for each individual case and the high frequency of pharmacoresistant cases. Therefore, the search for new drugs and methods of epilepsy treatment requires an advanced study of the molecular mechanisms of epileptogenesis. In this regard, the investigation of molecular chaperones as potential mediators of epileptogenesis seems promising because the chaperones are involved in the processing and regulation of the activity of many key proteins directly responsible for the generation of abnormal neuronal excitation in epilepsy. In this review, we try to systematize current data on the role of molecular chaperones in epileptogenesis and discuss the prospects for the use of chemical modulators of various chaperone groups' activity as promising antiepileptic drugs.
Topics: Humans; Epilepsy; Neurons; Molecular Chaperones
PubMed: 37755620
DOI: 10.1007/s12192-023-01378-1 -
The Journal of Biological Chemistry Aug 2020Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may... (Review)
Review
Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, -GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the "chaperone code."
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Processing, Post-Translational; Structure-Activity Relationship
PubMed: 32527727
DOI: 10.1074/jbc.REV120.011833 -
FEBS Letters Aug 2022Casein micelles are extracellular polydisperse assemblies of unstructured casein proteins. Caseins are the major component of milk. Within casein micelles, casein... (Review)
Review
Casein micelles are extracellular polydisperse assemblies of unstructured casein proteins. Caseins are the major component of milk. Within casein micelles, casein molecules are stabilised by binding to calcium phosphate nanoclusters and, by acting as molecular chaperones, through multivalent interactions. In the light of such interactions, we discuss whether casein micelles can be considered as extracellular condensates formed by liquid-liquid phase separation. We analyse the sequence, structure and interactions of caseins in comparison with proteins forming intracellular condensates. Furthermore, we review the similarities between caseins and small heat-shock proteins whose chaperone activity is linked to phase separation of proteins. By bringing these observations together, we describe a regulatory mechanism for protein condensates, as exemplified by casein micelles.
Topics: Animals; Caseins; Intrinsically Disordered Proteins; Micelles; Milk; Molecular Chaperones; Protein Folding
PubMed: 35815989
DOI: 10.1002/1873-3468.14449 -
Haematologica Jun 2021Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates.... (Review)
Review
Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70.
Topics: Animals; Erythroblasts; Erythrocytes; Erythropoiesis; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones
PubMed: 33832207
DOI: 10.3324/haematol.2019.233056 -
International Journal of Molecular... Oct 2019Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress... (Review)
Review
Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.
Topics: Antineoplastic Agents; Drug Therapy, Combination; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Isoxazoles; Molecular Chaperones; Neoplasms; Oligonucleotides; Resorcinols
PubMed: 31652993
DOI: 10.3390/ijms20215284 -
Cells May 2023Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Proteostasis; Molecular Chaperones; HSP40 Heat-Shock Proteins; Mutant Proteins
PubMed: 37174703
DOI: 10.3390/cells12091302 -
RNA Biology Jan 2021As a mental framework for the transition of self-replicating biological forms, the RNA world concept stipulates a dual function of RNAs as genetic substance and... (Review)
Review
As a mental framework for the transition of self-replicating biological forms, the RNA world concept stipulates a dual function of RNAs as genetic substance and catalyst. The chaperoning function is found intrinsic to ribozymes involved in protein synthesis and tRNA maturation, enriching the primordial RNA world with proteins of biological relevance. The ribozyme-resident protein folding activity, even before the advent of protein-based molecular chaperone, must have expedited the transition of the RNA world into the present protein theatre.
Topics: Animals; Host-Pathogen Interactions; Humans; Molecular Chaperones; Protein Binding; Protein Biosynthesis; Protein Folding; Proteins; RNA; RNA, Catalytic; RNA, Ribosomal
PubMed: 32781880
DOI: 10.1080/15476286.2020.1801199 -
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