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Journal of Molecular Biology Oct 2021Stunning advances have been achieved in addressing the protein folding problem, providing deeper understanding of the mechanisms by which proteins navigate energy... (Review)
Review
Stunning advances have been achieved in addressing the protein folding problem, providing deeper understanding of the mechanisms by which proteins navigate energy landscapes to reach their native states and enabling powerful algorithms to connect sequence to structure. However, the realities of the in vivo protein folding problem remain a challenge to reckon with. Here, we discuss the concept of the "proteome folding problem"-the problem of how organisms build and maintain a functional proteome-by admitting that folding energy landscapes are characterized by many misfolded states and that cells must deploy a network of chaperones and degradation enzymes to minimize deleterious impacts of these off-pathway species. The resulting proteostasis network is an inextricable part of in vivo protein folding and must be understood in detail if we are to solve the proteome folding problem. We discuss how the development of computational models for the proteostasis network's actions and the relationship to the biophysical properties of the proteome has begun to offer new insights and capabilities.
Topics: Animals; Humans; Molecular Chaperones; Protein Folding; Proteome; Proteostasis
PubMed: 34391802
DOI: 10.1016/j.jmb.2021.167197 -
Current Genetics Apr 2019The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many... (Review)
Review
The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many disease-related proteins including those in cancer. Substantial effort has been devoted to developing a range of chaperone inhibitors for clinical use. Recent studies have identified the oncogenic ribonucleotide reductase (RNR) complex as an interactor of chaperones. While several generations of RNR inhibitor have been developed for use in cancer patients, many of these produce severe side effects such as nausea, vomiting and hair loss. Development of more potent, less patient-toxic anti-RNR strategies would be highly desirable. Inhibition of chaperones and associated co-chaperone molecules in both cancer and model organisms such as budding yeast result in the destabilization of RNR subunits and a corresponding sensitization to RNR inhibitors. Going forward, this may form part of a novel strategy to target cancer cells that are resistant to standard RNR inhibitors.
Topics: Animals; Antineoplastic Agents; DNA Damage; DNA Replication; Enzyme Activation; Gene Expression Regulation; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms; Protein Binding; Proteomics; Ribonucleotide Reductases
PubMed: 30519713
DOI: 10.1007/s00294-018-0916-7 -
Cellular & Molecular Biology Letters 2016Bcl2-associated athanogene 2 (BAG2) shares a similar molecular structure and function with other BAG family members. Functioning as a co-chaperone, it interacts with the... (Review)
Review
Bcl2-associated athanogene 2 (BAG2) shares a similar molecular structure and function with other BAG family members. Functioning as a co-chaperone, it interacts with the ATPase domain of the heat shock protein 70 (dHsp70) through its BAG domain. It also interacts with many other molecules and regulates various cellular functions. An increasing number of studies have indicated that BAG2 is involved in the pathogenesis of various diseases, including cancers and neurodegenerative diseases. This paper is a comprehensive review of the structure, functions, and protein interactions of BAG2. We also discuss its roles in diseases, including cancer, Alzheimer's disease, Parkinson's disease and spinocerebellar ataxia type-3. Further research on BAG2 could lead to an understanding of the pathogenesis of these disorders or even to novel therapeutic approaches.
Topics: Animals; Humans; Molecular Chaperones; Neoplasms; Neurodegenerative Diseases; Protein Conformation
PubMed: 28536620
DOI: 10.1186/s11658-016-0020-2 -
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 -
Viruses Apr 2019Yeast prions are protein-based genetic elements found in the baker's yeast , most of which are amyloid aggregates that propagate by fragmentation and spreading of small,... (Review)
Review
Yeast prions are protein-based genetic elements found in the baker's yeast , most of which are amyloid aggregates that propagate by fragmentation and spreading of small, self-templating pieces called propagons. Fragmentation is carried out by molecular chaperones, specifically Hsp104, Hsp70, and Hsp40. Like other amyloid-forming proteins, amyloid-based yeast prions exhibit structural polymorphisms, termed "strains" in mammalian systems and "variants" in yeast, which demonstrate diverse phenotypes and chaperone requirements for propagation. Here, the known differential interactions between chaperone proteins and yeast prion variants are reviewed, specifically those of the yeast prions [], []/[], and [3]. For these prions, differences in variant-chaperone interactions (where known) with Hsp104, Hsp70s, Hsp40s, Sse1, and Hsp90 are summarized, as well as some interactions with chaperones of other species expressed in yeast. As amyloid structural differences greatly impact chaperone interactions, understanding and accounting for these variations may be crucial to the study of chaperones and both prion and non-prion amyloids.
Topics: Amyloid; Amyloidogenic Proteins; Models, Biological; Molecular Chaperones; Prions; Protein Interaction Domains and Motifs; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 30995727
DOI: 10.3390/v11040349 -
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 -
Cellular and Molecular Life Sciences :... Feb 2015Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein... (Review)
Review
Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of post-translational modifications in sHsp chaperone function, particularly in the context of disease.
Topics: Heat-Shock Proteins; Homeostasis; Humans; Models, Biological; Models, Molecular; Molecular Chaperones; Multiple Sclerosis; Neoplasms; Neurodegenerative Diseases; Phosphorylation; Polymerization; Protein Aggregation, Pathological; Protein Processing, Post-Translational; alpha-Crystallins
PubMed: 25352169
DOI: 10.1007/s00018-014-1754-5 -
Advances in Experimental Medicine and... 2016The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90... (Review)
Review
The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target.
Topics: HSP90 Heat-Shock Proteins; Humans; Macular Degeneration; Molecular Chaperones; Molecular Targeted Therapy; Pyridones; Pyrimidines; Retina; Retinal Diseases; Retinitis Pigmentosa; Vision, Ocular
PubMed: 26427407
DOI: 10.1007/978-3-319-17121-0_22 -
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 -
Trends in Microbiology Oct 2017Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with... (Review)
Review
Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with co-chaperones and by post-translational modifications. In the fungal pathogen Candida albicans, Hsp90 enables drug resistance and virulence by stabilizing diverse signal transducers. Here, we review studies that have unveiled regulators of Hsp90 function, as well as downstream effectors that govern the key virulence traits of morphogenesis and drug resistance. We highlight recent work mapping the Hsp90 genetic network in C. albicans under diverse environmental conditions, and how these interactions provide insight into circuitry important for drug resistance, morphogenesis, and virulence. Ultimately, elucidating the Hsp90 chaperone network will aid in the development of therapeutics to treat fungal disease.
Topics: Candida albicans; Drug Resistance, Fungal; Fungal Proteins; Gene Regulatory Networks; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Virulence
PubMed: 28549824
DOI: 10.1016/j.tim.2017.05.003