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1
Scalia, Federica, Alessandra Maria Vitale, Radha Santonocito, Everly Conway de Macario, Alberto J. L. Macario, and Francesco Cappello. "The Neurochaperonopathies: Anomalies of the Chaperone System with Pathogenic Effects in Neurodegenerative and Neuromuscular Disorders." Applied Sciences 11, no. 3 (January 20, 2021): 898. http://dx.doi.org/10.3390/app11030898.
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The chaperone (or chaperoning) system (CS) constitutes molecular chaperones, co-chaperones, and chaperone co-factors, interactors and receptors, and its canonical role is protein quality control. A malfunction of the CS may cause diseases, known as the chaperonopathies. These are caused by qualitatively and/or quantitatively abnormal molecular chaperones. Since the CS is ubiquitous, chaperonopathies are systemic, affecting various tissues and organs, playing an etiologic-pathogenic role in diverse conditions. In this review, we focus on chaperonopathies involved in the pathogenic mechanisms of diseases of the central and peripheral nervous systems: the neurochaperonopathies (NCPs). Genetic NCPs are linked to pathogenic variants of chaperone genes encoding, for example, the small Hsp, Hsp10, Hsp40, Hsp60, and CCT-BBS (chaperonin-containing TCP-1- Bardet–Biedl syndrome) chaperones. Instead, the acquired NCPs are associated with malfunctional chaperones, such as Hsp70, Hsp90, and VCP/p97 with aberrant post-translational modifications. Awareness of the chaperonopathies as the underlying primary or secondary causes of disease will improve diagnosis and patient management and open the possibility of investigating and developing chaperonotherapy, namely treatment with the abnormal chaperone as the main target. Positive chaperonotherapy would apply in chaperonopathies by defect, i.e., chaperone insufficiency, and consist of chaperone replacement or boosting, whereas negative chaperonotherapy would be pertinent when a chaperone actively participates in the initiation and progression of the disease and must be blocked and eliminated.
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Hervás, Rubén, and Javier Oroz. "Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly." International Journal of Molecular Sciences 21, no. 23 (December 2, 2020): 9186. http://dx.doi.org/10.3390/ijms21239186.
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Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.
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Zuehlke, Abbey D., Michael A. Moses, and Len Neckers. "Heat shock protein 90: its inhibition and function." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1738 (December 4, 2017): 20160527. http://dx.doi.org/10.1098/rstb.2016.0527.
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The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone–assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states. Many of the proteins chaperoned by Hsp90 (Hsp90 clients) are essential for the progression of various diseases, including cancer, Alzheimer's disease and other neurodegenerative diseases, as well as viral and bacterial infections. Given the importance of these clients in different diseases and their dynamic interplay with the chaperone machinery, it has been suggested that targeting Hsp90 and its respective co-chaperones may be an effective method for combating a large range of illnesses. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
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Chen, Chih-Ling, Chien-Nan Lee, Yin-Hsiu Chien, Wuh-Liang Hwu, Tung-Ming Chang, and Ni-Chung Lee. "Novel Compound Heterozygous Variants in TBCD Gene Associated with Infantile Neurodegenerative Encephalopathy." Children 8, no. 12 (December 5, 2021): 1140. http://dx.doi.org/10.3390/children8121140.
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Mutations in tubulin-specific chaperon D (TBCD), the gene encoding one of the co-chaperons required for the assembly and disassembly of the α/β-tubulin heterodimers, have been reported to cause perturbed microtubule dynamics, resulting in debilitating early-onset progressive neurodegenerative disorder. Here, we identified two novel TBCD variants, c.1340C>T (p.Ala447Val), and c.817+2T>C, presented as compound heterozygotes in two affected siblings born to unaffected carrier parents. Clinical features included early-onset neurodegeneration, failure to thrive, respiratory failure, hypotonia, muscle weakness and atrophy and seizures. We established the genotype–phenotype relationship of these TBCD pathogenic variants and provided insight into the protein structural alteration that may contribute to this chaperone-associated tubulinopathy.
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Wang, Lisha, Liza Bergkvist, Rajnish Kumar, Bengt Winblad, and Pavel F. Pavlov. "Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases." Cells 10, no. 10 (September 29, 2021): 2596. http://dx.doi.org/10.3390/cells10102596.
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The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.
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Stemp, Markus J., Suranjana Guha, F. Ulrich Hartl, and José M. Barral. "Efficient production of native actin upon translation in a bacterial lysate supplemented with the eukaryotic chaperonin TRiC." Biological Chemistry 386, no. 8 (August 1, 2005): 753–57. http://dx.doi.org/10.1515/bc.2005.088.
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Abstract Recombinant expression of actin in bacteria results in non-native species that aggregate into inclusion bodies. Actin is a folding substrate of TRiC, the chaperonin of the eukaryotic cytosol. By employing bacterial in vitro translation lysates supplemented with purified chaperones, we have found that TRiC is the only eukaryotic chaperone necessary for correct folding of newly translated actin. The actin thus produced binds deoxyribonuclease I and polymerizes into filaments, hallmarks of its native state. In contrast to its rapid folding in the eukaryotic cytosol, actin translated in TRiC-supplemented bacterial lysate folds with slower kinetics, resembling the kinetics upon refolding from denaturant. Lysate supplementation with the bacterial chaperonin GroEL/ES or the DnaK/DnaJ/GrpE chaperones leads to prevention of actin aggregation, yet fails to support its correct folding. This combination of in vitro bacterial translation and TRiC-assisted folding allows a detailed analysis of the mechanisms necessary for efficient actin folding in vivo. In addition, it provides a robust alternative for the production of substantial amounts of eukaryotic proteins that otherwise misfold or lead to cellular toxicity upon expression in heterologous hosts.
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Lin, Jiusheng, and Mark A. Wilson. "Escherichia coli Thioredoxin-like Protein YbbN Contains an Atypical Tetratricopeptide Repeat Motif and Is a Negative Regulator of GroEL." Journal of Biological Chemistry 286, no. 22 (April 15, 2011): 19459–69. http://dx.doi.org/10.1074/jbc.m111.238741.
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Many proteins contain a thioredoxin (Trx)-like domain fused with one or more partner domains that diversify protein function by the modular construction of new molecules. The Escherichia coli protein YbbN is a Trx-like protein that contains a C-terminal domain with low homology to tetratricopeptide repeat motifs. YbbN has been proposed to act as a chaperone or co-chaperone that aids in heat stress response and DNA synthesis. We report the crystal structure of YbbN, which is an elongated molecule with a mobile Trx domain and four atypical tetratricopeptide repeat motifs. The Trx domain lacks a canonical CXXC active site architecture and is not a functional oxidoreductase. A variety of proteins in E. coli interact with YbbN, including multiple ribosomal protein subunits and a strong interaction with GroEL. YbbN acts as a mild inhibitor of GroESL chaperonin function and ATPase activity, suggesting that it is a negative regulator of the GroESL system. Combined with previous observations that YbbN enhances the DnaK-DnaJ-GrpE chaperone system, we propose that YbbN coordinately regulates the activities of these two prokaryotic chaperones, thereby helping to direct client protein traffic initially to DnaK. Therefore, YbbN may play a role in integrating the activities of different chaperone pathways in E. coli and related bacteria.
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Griffith, Alijah A., and William Holmes. "Fine Tuning: Effects of Post-Translational Modification on Hsp70 Chaperones." International Journal of Molecular Sciences 20, no. 17 (August 28, 2019): 4207. http://dx.doi.org/10.3390/ijms20174207.
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The discovery of heat shock proteins shaped our view of protein folding in the cell. Since their initial discovery, chaperone proteins were identified in all domains of life, demonstrating their vital and conserved functional roles in protein homeostasis. Chaperone proteins maintain proper protein folding in the cell by utilizing a variety of distinct, characteristic mechanisms to prevent aberrant intermolecular interactions, prevent protein aggregation, and lower entropic costs to allow for protein refolding. Continued study has found that chaperones may exhibit alternative functions, including maintaining protein folding during endoplasmic reticulum (ER) import and chaperone-mediated degradation, among others. Alternative chaperone functions are frequently controlled by post-translational modification, in which a given chaperone can switch between functions through covalent modification. This review will focus on the Hsp70 class chaperones and their Hsp40 co-chaperones, specifically highlighting the importance of post-translational control of chaperones. These modifications may serve as a target for therapeutic intervention in the treatment of diseases of protein misfolding and aggregation.
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Ellis, R. John. "Assembly chaperones: a perspective." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1617 (May 5, 2013): 20110398. http://dx.doi.org/10.1098/rstb.2011.0398.
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The historical origins and current interpretation of the molecular chaperone concept are presented, with the emphasis on the distinction between folding chaperones and assembly chaperones. Definitions of some basic terms in this field are offered and misconceptions pointed out. Two examples of assembly chaperone are discussed in more detail: the role of numerous histone chaperones in fundamental nuclear processes and the co-operation of assembly chaperones with folding chaperones in the production of the world's most important enzyme.
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Matsukura, L., and N. Miyashita. "Simulation study of the function of domain swapping in the HSP90 chaperone cycle." Journal of Physics: Conference Series 2207, no. 1 (March 1, 2022): 012024. http://dx.doi.org/10.1088/1742-6596/2207/1/012024.
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Abstract HSP90 is one of the molecular chaperones, and it is known as an anti-cancer drug target. In the HSP90 chaperone cycle, when the ATP binds to the HSP90NTD, the HSP90 dimer forms a domain swapping in NTD. The stability of the HSP90 dimer is essential to the HSP90 chaperon cycle process. We have performed several molecular dynamics simulations of the HSP90 dimer to investigate how ATP binding and domain swapping have affected the stability. We analysed the fluctuation of critical residues for ATP binding and ATP hydrolysis in the HSP90NTD dimer conformation. As a result, we found that domain swapping is essential to the stability of the HSP90 dimer, while ATP is not so essential for the stability of the dimer conformation.
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Altinok, Selin, Rebekah Sanchez-Hodge, Mariah Stewart, Kaitlan Smith, and Jonathan C. Schisler. "With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage." Cells 10, no. 11 (November 11, 2021): 3121. http://dx.doi.org/10.3390/cells10113121.
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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
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Scalia, Federica, Antonella Marino Gammazza, Everly Conway de Macario, Alberto J. L. Macario, and Francesco Cappello. "Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy." Brain Sciences 9, no. 11 (October 30, 2019): 297. http://dx.doi.org/10.3390/brainsci9110297.
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The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment.
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Modgil, V., R. Barratt, DJ Summerton, and A. Muneer. "Chaperone use amongst UK urological surgeons – an evaluation of current practice and opinion." Annals of The Royal College of Surgeons of England 98, no. 04 (April 1, 2016): 268–69. http://dx.doi.org/10.1308/rcsann.2016.0071.
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Introduction Intimate examinations are routinely performed by urologists as part of clinical practice. To protect patients and doctors, the General Medical Council offers guidance on the use of chaperones for intimate examinations. We assessed the opinions and use of chaperones amongst members of the British Association of Urological Surgeons (BAUS). Methods An online questionnaire comprising 12 questions on the use of chaperones in clinical practice was sent to all full, trainee and speciality doctor members of BAUS. Results The questionnaire had a response rate of 26% (n=331). The majority of respondents were consultant urologists, comprising 78.8% (n=261), with a wide range of years of experience. Of the respondents, 38.9% were not aware of the GMC guidance on chaperones. While 72.5% always used a chaperone., 22.9% never use a chaperone when the patient was of the same sex. Chaperones were most commonly used for intimate examinations (64.6%), and for examinations involving members of the opposite sex (77.3%). A majority of respondents felt that chaperones protect both the patient (77.3%), and the doctor (96.6%). However, 42.5% did not feel that using a chaperone assists the doctor’s examination, and some (17.2%) participants felt that chaperones were unnecessary. Conclusions This study shows considerable variability amongst urologists in their use of chaperones. A significant proportion of respondents were not aware of the GMC guidelines and did not regularly use a chaperone during an intimate examination. In addition, practice appears to be gender biased. Further study and education is suggested.
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Kettern, Nadja, Michael Dreiseidler, Riga Tawo, and Jörg Höhfeld. "Chaperone-assisted degradation: multiple paths to destruction." Biological Chemistry 391, no. 5 (May 1, 2010): 481–89. http://dx.doi.org/10.1515/bc.2010.058.
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Abstract Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP (chaperone-assisted proteasomal degradation), CASA (chaperone-assisted selective autophagy), and CMA (chaperone-mediated autophagy). Within these pathways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.
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Meimaridou, Eirini, Sakina B. Gooljar, and J. Paul Chapple. "From hatching to dispatching: the multiple cellular roles of the Hsp70 molecular chaperone machinery." Journal of Molecular Endocrinology 42, no. 1 (October 13, 2008): 1–9. http://dx.doi.org/10.1677/jme-08-0116.
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Molecular chaperones are best recognized for their roles in de novo protein folding and the cellular response to stress. However, many molecular chaperones, and in particular the Hsp70 chaperone machinery, have multiple diverse cellular functions. At the molecular level, chaperones are mediators of protein conformational change. To facilitate conformational change of client/substrate proteins, in manifold contexts, chaperone power must be closely regulated and harnessed to specific cellular locales – this is controlled by cochaperones. This review considers specialized functions of the Hsp70 chaperone machinery mediated by its cochaperones. We focus on vesicular trafficking, protein degradation and a potential role in G protein-coupled receptor processing.
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Alvarez-Ponce, David, José Aguilar-Rodríguez, and Mario A. Fares. "Molecular Chaperones Accelerate the Evolution of Their Protein Clients in Yeast." Genome Biology and Evolution 11, no. 8 (July 11, 2019): 2360–75. http://dx.doi.org/10.1093/gbe/evz147.
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Abstract Protein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone–protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence of Saccharomyces cerevisiae and S. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains of S. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding non-client proteins when controlling for their number of protein–protein interactions. We also find that genes encoding client proteins have accumulated more intraspecific genetic diversity than those encoding non-client proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype–phenotype maps, have a considerable accelerating effect on protein evolution.
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Eggers, D. K., W. J. Welch, and W. J. Hansen. "Complexes between nascent polypeptides and their molecular chaperones in the cytosol of mammalian cells." Molecular Biology of the Cell 8, no. 8 (August 1997): 1559–73. http://dx.doi.org/10.1091/mbc.8.8.1559.
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Folding of newly synthesized proteins in vivo is believed to be facilitated by the cooperative interaction of a defined group of proteins known as molecular chaperones. We investigated the direct interaction of chaperones with nascent polypeptides in the cytosol of mammalian cells by multiple methods. A new approach using a polyclonal antibody to puromycin allowed us to tag and capture a population of truncated nascent polypeptides with no bias as to the identity of the bound chaperones. In addition, antibodies that recognize the cytosolic chaperones hsp70, CCT (TRiC), hsp40, p48 (Hip), and hsp90 were compared on the basis of their ability to coprecipitate nascent polypeptides, both before and after chemical cross-linking. By all three approaches, hsp70 was found to be the predominant chaperone bound to nascent polypeptides. The interaction between hsp70 and nascent polypeptides is apparently dynamic under physiological conditions but can be stabilized by depletion of ATP or by cross-linking. The cytosolic chaperonin CCT was found to bind primarily to full-length, newly synthesized actin, and tubulin. We demonstrate and caution that nascent polypeptides have a propensity for binding many proteins nonspecifically in cell lysates. Although current models of protein folding in vivo have described additional components in contact with nascent polypeptides, our data indicate that the hsp70 and, perhaps, the hsp90 families are the predominant classes of molecular chaperones that interact with the general population of cytosolic nascent polypeptides.
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Paladino, Letizia, Alessandra Vitale, Radha Santonocito, Alessandro Pitruzzella, Calogero Cipolla, Giuseppa Graceffa, Fabio Bucchieri, Everly Conway de Macario, Alberto Macario, and Francesca Rappa. "Molecular Chaperones and Thyroid Cancer." International Journal of Molecular Sciences 22, no. 8 (April 18, 2021): 4196. http://dx.doi.org/10.3390/ijms22084196.
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Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of the chaperone system (CS). Components of the CS are found to be quantitatively increased or decreased, and some correlations have been established between the quantitative changes and tumor type, prognosis, and response to treatment. These correlations provide the basis for identifying distinctive patterns useful in differential diagnosis and for planning experiments aiming at elucidating the role of the CS in tumorigenesis. Here, we discuss studies of the CS components in various thyroid cancers (TC). The chaperones belonging to the families of the small heat-shock proteins Hsp70 and Hsp90 and the chaperonin of Group I, Hsp60, have been quantified mostly by immunohistochemistry and Western blot in tumor and normal control tissues and in extracellular vesicles. Distinctive differences were revealed between the various thyroid tumor types. The most frequent finding was an increase in the chaperones, which can be attributed to the augmented need for chaperones the tumor cells have because of their accelerated metabolism, growth, and division rate. Thus, chaperones help the tumor cell rather than protect the patient, exemplifying chaperonopathies by mistake or collaborationism. This highlights the need for research on chaperonotherapy, namely the development of means to eliminate/inhibit pathogenic chaperones.
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Estorninho, Megan, Hilde Smith, Jelle Thole, Jose Harders-Westerveen, Andrzej Kierzek, Rachel E. Butler, Olivier Neyrolles, and Graham R. Stewart. "ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage." Microbiology 156, no. 11 (November 1, 2010): 3445–55. http://dx.doi.org/10.1099/mic.0.042275-0.
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Chaperone and protease systems play essential roles in cellular homeostasis and have vital functions in controlling the abundance of specific cellular proteins involved in processes such as transcription, replication, metabolism and virulence. Bacteria have evolved accurate regulatory systems to control the expression and function of chaperones and potentially destructive proteases. Here, we have used a combination of transcriptomics, proteomics and targeted mutagenesis to reveal that the clp gene regulator (ClgR) of Mycobacterium tuberculosis activates the transcription of at least ten genes, including four that encode protease systems (ClpP1/C, ClpP2/C, PtrB and HtrA-like protease Rv1043c) and three that encode chaperones (Acr2, ClpB and the chaperonin Rv3269). Thus, M. tuberculosis ClgR controls a larger network of protein homeostatic and regulatory systems than ClgR in any other bacterium studied to date. We demonstrate that ClgR-regulated transcriptional activation of these systems is essential for M. tuberculosis to replicate in macrophages. Furthermore, we observe that this defect is manifest early in infection, as M. tuberculosis lacking ClgR is deficient in the ability to control phagosome pH 1 h post-phagocytosis.
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Csermely, Peter. "A Nonconventional Role of Molecular Chaperones: Involvement in the Cytoarchitecture." Physiology 16, no. 3 (June 2001): 123–26. http://dx.doi.org/10.1152/physiologyonline.2001.16.3.123.
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A hallmark of chaperone action is assistance in protein folding. Indeed, folding of nascent prokaryotic proteins proceeds mostly as a chaperone-assisted, posttranslational event. On the contrary, in nonstressed eukaryotic cells folding-related tasks of eukaryotic chaperones are restricted to a subset of proteins, and “jobless” chaperones may form an extension of the cytoarchitecture, facilitating intracellular traffic of proteins and other macromolecules.
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Killian, Andrea N., Sarah C. Miller, and Justin K. Hines. "Impact of Amyloid Polymorphism on Prion-Chaperone Interactions in Yeast." Viruses 11, no. 4 (April 16, 2019): 349. http://dx.doi.org/10.3390/v11040349.
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Yeast prions are protein-based genetic elements found in the baker’s yeast Saccharomyces cerevisiae, 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 [PSI+], [RNQ+]/[PIN+], and [URE3]. 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.
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Li, Fazhao, Han Xiao, Fangfang Zhou, Zhiping Hu, and Binbin Yang. "Study of HSPB6: Insights into the Properties of the Multifunctional Protective Agent." Cellular Physiology and Biochemistry 44, no. 1 (2017): 314–32. http://dx.doi.org/10.1159/000484889.
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HSPB6(Heat shock protein B6), is also referred to as P20/HSP20. Unlike other many other members of sHSP(small Heat shock protein) family, which tend to form high-molecular-mass oligomers, in solution, human HSPB6 only forms dimers. However, it still exhibits chaperon-like activity comparable with that of HSPB5. It is expressed ubiquitously, with high and constitutive expression in muscular tissues. sHSPs characteristically function as molecular chaperones and HSPB6 also has a molecular chaperone activity. HSPB6 is up-regulated in response to diverse cellular stress or damage and protect cells from otherwise lethal conditions. HSPB6 is widely recognized as a principle mediator of cardioprotective signaling and recent studies have unraveled the protective role of HSPB6 in disease or injury to the central nervous system. Moreover, accumulating evidence has implicated HSPB6 as a key mediator of diverse vital physiological processes, such as smooth muscle relaxation, platelet aggregation. The versatility of HSPB6 can be explained by its direct involvement in regulating different client proteins and its ability to form heterooligomer with other sHSPs, which seems to be dependent on HSPB6 phosphorylation. This review focuses on the properties including expression and regulation pattern, phosphorylation, chaperon activity, multiple cellular targets of HSPB6, as well as its possible role in physical and pathological conditions.
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Quinlan, Roy A., and R. John Ellis. "Chaperones: needed for both the good times and the bad times." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1617 (May 5, 2013): 20130091. http://dx.doi.org/10.1098/rstb.2013.0091.
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In this issue, we explore the assembly roles of protein chaperones, mainly through the portal of their associated human diseases (e.g. cardiomyopathy, cataract, neurodegeneration, cancer and neuropathy). There is a diversity to chaperone function that goes beyond the current emphasis in the scientific literature on their undoubted roles in protein folding and refolding. The focus on chaperone-mediated protein folding needs to be broadened by the original Laskey discovery that a chaperone assists the assembly of an oligomeric structure, the nucleosome, and the subsequent suggestion by Ellis that other chaperones may function in assembly processes, as well as in folding. There have been a number of recent discoveries that extend this relatively neglected aspect of chaperone biology to include proteostasis, maintenance of the cellular redox potential, genome stability, transcriptional regulation and cytoskeletal dynamics. So central are these processes that we propose that chaperones stand at the crossroads of life and death because they mediate essential functions, not only during the bad times, but also in the good times. We suggest that chaperones facilitate the success of a species, and hence the evolution of individuals within populations, because of their contributions to so many key cellular processes, of which protein folding is only one.
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Maslova, Ekaterina, Evgeny Pichkur, Pavel Semenyuk, Lidia Kurochkina, and Olga Sokolova. "Abstract P-45: Structure of the Bacteriophage AR9 Bacillus Subtilis Chaperonin According to Cryo-Electron Microscopy." International Journal of Biomedicine 11, Suppl_1 (June 1, 2021): S32. http://dx.doi.org/10.21103/ijbm.11.suppl_1.p45.
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Background: Chaperonins are a family of molecular chaperones Hsp60 (heat shock proteins 60). GroEL is a bacterial chaperonin. It ensures the correct folding of proteins, using the energy of ATP hydrolysis. Three-dimensional reconstructions of its predicted orthologs were obtained and biochemically characterized in free and nucleotide-bound states for bacteriophages EL Pseudomonas aeruginosa, OBP Pseudomonas fluorescens (Kurochkina, L. P. et al., Journal of virology, 2012; Semenyuk, P. I. et al., Biochemical Journal, 2016; Stanishneva-Konovalova, T. B. et al., Journal of Structural Biology, 2020). Physicochemical studies were carried out for the bacteriophage AR9 Bacillus Subtilis and confirmed that the protein has chaperone activity and does not require co-chaperonin to function (Semenyuk P. I. et al., International Journal of Biological Macromolecules, 2020). Methods: The recombinant chaperonin of the B. subtilis bacterial phage AR9 (gp228) was isolated and purified in a free state and vitrified in Vitrobot Mark IV. Data were collected using a Titan Krios cryo-TEM and processed in Warp, RELION and cryoSPARC software. Results: The final structures of the chaperonin were reconstructed with a C1 and C7 symmetry at the resolution of 4.5 Å and 4.0 Å respectively. Significant heterogeneity of the apical domains was addressed further using 3D classification and symmetry expansion in RELION resulting in a set of classes reflecting the conformational transition of the subunits between different states. At least four different conformational states of the subunit were clearly resolved. Conclusion: Gp228 structure show similarities between bacteriophage chaperonin and also bacterial chaperonin GroEL. It is formed by a single ring consisting of seven identical subunits, each has three domains: equatorial, intermediate, and apical. The subunits of the apo-form chaperonin Gp228 exhibit significant conformational flexibility in the apical and intermediate domains.
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Chakrabarti, Shaon, Changbong Hyeon, Xiang Ye, George H. Lorimer, and D. Thirumalai. "Molecular chaperones maximize the native state yield on biological times by driving substrates out of equilibrium." Proceedings of the National Academy of Sciences 114, no. 51 (December 7, 2017): E10919—E10927. http://dx.doi.org/10.1073/pnas.1712962114.
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Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding ofTetrahymenaribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the yield of native states depends on chaperone concentration. Although the absolute yield of native states decreases in theTetrahymenaribozyme, the product of the folding rate and the steady-state native yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.
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Bui, Le Minh, Almando Geraldi, Thi Thuy Nguyen, Jun Hyoung Lee, Ju Young Lee, Byung-Kwan Cho, and Sun Chang Kim. "mRNA Engineering for the Efficient Chaperone-Mediated Co-Translational Folding of Recombinant Proteins in Escherichia coli." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3163. http://dx.doi.org/10.3390/ijms20133163.
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The production of soluble, functional recombinant proteins by engineered bacterial hosts is challenging. Natural molecular chaperone systems have been used to solubilize various recombinant proteins with limited success. Here, we attempted to facilitate chaperone-mediated folding by directing the molecular chaperones to their protein substrates before the co-translational folding process completed. To achieve this, we either anchored the bacterial chaperone DnaJ to the 3ʹ untranslated region of a target mRNA by fusing with an RNA-binding domain in the chaperone-recruiting mRNA scaffold (CRAS) system, or coupled the expression of DnaJ and a target recombinant protein using the overlapping stop-start codons 5ʹ-TAATG-3ʹ between the two genes in a chaperone-substrate co-localized expression (CLEX) system. By engineering the untranslated and intergenic sequences of the mRNA transcript, bacterial molecular chaperones are spatially constrained to the location of protein translation, expressing selected aggregation-prone proteins in their functionally active, soluble form. Our mRNA engineering methods surpassed the in-vivo solubilization efficiency of the simple DnaJ chaperone co-overexpression method, thus providing more effective tools for producing soluble therapeutic proteins and enzymes.
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Bohush, Anastasiia, Paweł Bieganowski, and Anna Filipek. "Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases." International Journal of Molecular Sciences 20, no. 20 (October 9, 2019): 4976. http://dx.doi.org/10.3390/ijms20204976.
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Proper folding is crucial for proteins to achieve functional activity in the cell. However, it often occurs that proteins are improperly folded (misfolded) and form aggregates, which are the main hallmark of many diseases including cancers, neurodegenerative diseases and many others. Proteins that assist other proteins in proper folding into three-dimensional structures are chaperones and co-chaperones. The key role of chaperones/co-chaperones is to prevent protein aggregation, especially under stress. An imbalance between chaperone/co-chaperone levels has been documented in neurons, and suggested to contribute to protein misfolding. An essential protein and a major regulator of protein folding in all eukaryotic cells is the heat shock protein 90 (Hsp90). The function of Hsp90 is tightly regulated by many factors, including co-chaperones. In this review we summarize results regarding the role of Hsp90 and its co-chaperones in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and prionopathies.
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He, Wei, Jiayin Zhang, Veronika Sachsenhauser, Lili Wang, James C. A. Bardwell, and Shu Quan. "Increased surface charge in the protein chaperone Spy enhances its anti-aggregation activity." Journal of Biological Chemistry 295, no. 42 (August 17, 2020): 14488–500. http://dx.doi.org/10.1074/jbc.ra119.012300.
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Chaperones are essential components of the protein homeostasis network. There is a growing interest in optimizing chaperone function, but exactly how to achieve this aim is unclear. Here, using a model chaperone, the bacterial protein Spy, we demonstrate that substitutions that alter the electrostatic potential of Spy's concave, client-binding surface enhance Spy's anti-aggregation activity. We show that this strategy is more efficient than one that enhances the hydrophobicity of Spy's surface. Our findings thus challenge the traditional notion that hydrophobic interactions are the major driving forces that guide chaperone–substrate binding. Kinetic data revealed that both charge- and hydrophobicity-enhanced Spy variants release clients more slowly, resulting in a greater “holdase” activity. However, increasing short-range hydrophobic interactions deleteriously affected Spy's ability to capture substrates, thus reducing its in vitro chaperone activity toward fast-aggregating substrates. Our strategy in chaperone surface engineering therefore sought to fine-tune the different molecular forces involved in chaperone–substrate interactions rather than focusing on enhancing hydrophobic interactions. These results improve our understanding of the mechanistic basis of chaperone–client interactions and illustrate how protein surface–based mutational strategies can facilitate the rational improvement of molecular chaperones.
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Macario, Alberto J. L., Marianne Lange, Birgitte K. Ahring, and Everly Conway De Macario. "Stress Genes and Proteins in the Archaea." Microbiology and Molecular Biology Reviews 63, no. 4 (December 1, 1999): 923–67. http://dx.doi.org/10.1128/mmbr.63.4.923-967.1999.
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SUMMARY The field covered in this review is new; the first sequence of a gene encoding the molecular chaperone Hsp70 and the first description of a chaperonin in the archaea were reported in 1991. These findings boosted research in other areas beyond the archaea that were directly relevant to bacteria and eukaryotes, for example, stress gene regulation, the structure-function relationship of the chaperonin complex, protein-based molecular phylogeny of organisms and eukaryotic-cell organelles, molecular biology and biochemistry of life in extreme environments, and stress tolerance at the cellular and molecular levels. In the last 8 years, archaeal stress genes and proteins belonging to the families Hsp70, Hsp60 (chaperonins), Hsp40(DnaJ), and small heat-shock proteins (sHsp) have been studied. The hsp70(dnaK), hsp40(dnaJ), and grpE genes (the chaperone machine) have been sequenced in seven, four, and two species, respectively, but their expression has been examined in detail only in the mesophilic methanogen Methanosarcina mazei S-6. The proteins possess markers typical of bacterial homologs but none of the signatures distinctive of eukaryotes. In contrast, gene expression and transcription initiation signals and factors are of the eucaryal type, which suggests a hybrid archaeal-bacterial complexion for the Hsp70 system. Another remarkable feature is that several archaeal species in different phylogenetic branches do not have the gene hsp70(dnaK), an evolutionary puzzle that raises the important question of what replaces the product of this gene, Hsp70(DnaK), in protein biogenesis and refolding and for stress resistance. Although archaea are prokaryotes like bacteria, their Hsp60 (chaperonin) family is of type (group) II, similar to that of the eukaryotic cytosol; however, unlike the latter, which has several different members, the archaeal chaperonin system usually includes only two (in some species one and in others possibly three) related subunits of ∼60 kDa. These form, in various combinations depending on the species, a large structure or chaperonin complex sometimes called the thermosome. This multimolecular assembly is similar to the bacterial chaperonin complex GroEL/S, but it is made of only the large, double-ring oligomers each with eight (or nine) subunits instead of seven as in the bacterial complex. Like Hsp70(DnaK), the archaeal chaperonin subunits are remarkable for their evolution, but for a different reason. Ubiquitous among archaea, the chaperonins show a pattern of recurrent gene duplication—hetero-oligomeric chaperonin complexes appear to have evolved several times independently. The stress response and stress tolerance in the archaea involve chaperones, chaperonins, other heat shock (stress) proteins including sHsp, thermoprotectants, the proteasome, as yet incompletely understood thermoresistant features of many molecules, and formation of multicellular structures. The latter structures include single- and mixed-species (bacterial-archaeal) types. Many questions remain unanswered, and the field offers extraordinary opportunities owing to the diversity, genetic makeup, and phylogenetic position of archaea and the variety of ecosystems they inhabit. Specific aspects that deserve investigation are elucidation of the mechanism of action of the chaperonin complex at different temperatures, identification of the partners and substitutes for the Hsp70 chaperone machine, analysis of protein folding and refolding in hyperthermophiles, and determination of the molecular mechanisms involved in stress gene regulation in archaeal species that thrive under widely different conditions (temperature, pH, osmolarity, and barometric pressure). These studies are now possible with uni- and multicellular archaeal models and are relevant to various areas of basic and applied research, including exploration and conquest of ecosystems inhospitable to humans and many mammals and plants.
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Liang, Fu-Cheng, Gerard Kroon, Camille Z. McAvoy, Chris Chi, Peter E. Wright, and Shu-ou Shan. "Conformational dynamics of a membrane protein chaperone enables spatially regulated substrate capture and release." Proceedings of the National Academy of Sciences 113, no. 12 (March 7, 2016): E1615—E1624. http://dx.doi.org/10.1073/pnas.1524777113.
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Membrane protein biogenesis poses enormous challenges to cellular protein homeostasis and requires effective molecular chaperones. Compared with chaperones that promote soluble protein folding, membrane protein chaperones require tight spatiotemporal coordination of their substrate binding and release cycles. Here we define the chaperone cycle for cpSRP43, which protects the largest family of membrane proteins, the light harvesting chlorophyll a/b-binding proteins (LHCPs), during their delivery. Biochemical and NMR analyses demonstrate that cpSRP43 samples three distinct conformations. The stromal factor cpSRP54 drives cpSRP43 to the active state, allowing it to tightly bind substrate in the aqueous compartment. Bidentate interactions with the Alb3 translocase drive cpSRP43 to a partially inactive state, triggering selective release of LHCP’s transmembrane domains in a productive unloading complex at the membrane. Our work demonstrates how the intrinsic conformational dynamics of a chaperone enables spatially coordinated substrate capture and release, which may be general to other ATP-independent chaperone systems.
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Sarowar, Samema, Olivia J. Hu, Glenn T. Werneburg, David G. Thanassi, and Huilin Li. "The Escherichia coli P and Type 1 Pilus Assembly Chaperones PapD and FimC Are Monomeric in Solution." Journal of Bacteriology 198, no. 17 (June 27, 2016): 2360–69. http://dx.doi.org/10.1128/jb.00366-16.
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ABSTRACTThe chaperone/usher pathway is used by Gram-negative bacteria to assemble adhesive surface structures known as pili or fimbriae. Uropathogenic strains ofEscherichia coliuse this pathway to assemble P and type 1 pili, which facilitate colonization of the kidney and bladder, respectively. Pilus assembly requires a periplasmic chaperone and outer membrane protein termed the usher. The chaperone allows folding of pilus subunits and escorts the subunits to the usher for polymerization into pili and secretion to the cell surface. Based on previous structures of mutant versions of the P pilus chaperone PapD, it was suggested that the chaperone dimerizes in the periplasm as a self-capping mechanism. Such dimerization is counterintuitive because the chaperone G1 strand, important for chaperone-subunit interaction, is buried at the dimer interface. Here, we show that the wild-type PapD chaperone also forms a dimer in the crystal lattice; however, the dimer interface is different from the previously solved structures. In contrast to the crystal structures, we found that both PapD and the type 1 pilus chaperone, FimC, are monomeric in solution. Our findings indicate that pilus chaperones do not sequester their G1 β-strand by forming a dimer. Instead, the chaperones may expose their G1 strand for facile interaction with pilus subunits. We also found that the type 1 pilus adhesin, FimH, is flexible in solution while in complex with its chaperone, whereas the P pilus adhesin, PapGII, is rigid. Our study clarifies a crucial step in pilus biogenesis and reveals pilus-specific differences that may relate to biological function.IMPORTANCEPili are critical virulence factors for many bacterial pathogens. UropathogenicE. colirelies on P and type 1 pili assembled by the chaperone/usher pathway to adhere to the urinary tract and establish infection. Studying pilus assembly is important for understanding mechanisms of protein secretion, as well as for identifying points for therapeutic intervention. Pilus biogenesis is a multistep process. This work investigates the oligomeric state of the pilus chaperone in the periplasm, which is important for understanding early assembly events. Our work unambiguously demonstrates that both PapD and FimC chaperones are monomeric in solution. We further demonstrate that the solution behavior of the FimH and PapGII adhesins differ, which may be related to functional differences between the two pilus systems.
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Sala, Ambre Julie, Patricia Bordes, Sara Ayala, Nawel Slama, Samuel Tranier, Michèle Coddeville, Anne-Marie Cirinesi, Marie-Pierre Castanié-Cornet, Lionel Mourey, and Pierre Genevaux. "Directed evolution of SecB chaperones toward toxin-antitoxin systems." Proceedings of the National Academy of Sciences 114, no. 47 (November 7, 2017): 12584–89. http://dx.doi.org/10.1073/pnas.1710456114.
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SecB chaperones assist protein export in bacteria. However, certain SecB family members have diverged to become specialized toward the control of toxin-antitoxin (TA) systems known to promote bacterial adaptation to stress and persistence. In such tripartite TA-chaperone (TAC) systems, the chaperone was shown to assist folding and to prevent degradation of its cognate antitoxin, thus facilitating inhibition of the toxin. Here, we used both the export chaperone SecB ofEscherichia coliand the tripartite TAC system ofMycobacterium tuberculosisas a model to investigate how generic chaperones can specialize toward the control of TA systems. Through directed evolution of SecB, we have identified and characterized mutations that specifically improve the ability of SecB to control our model TA system without affecting its function in protein export. Such a remarkable plasticity of SecB chaperone function suggests that its substrate binding surface can be readily remodeled to accommodate specific clients.
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He, Lichun, Timothy Sharpe, Adam Mazur, and Sebastian Hiller. "A molecular mechanism of chaperone-client recognition." Science Advances 2, no. 11 (November 2016): e1601625. http://dx.doi.org/10.1126/sciadv.1601625.
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Molecular chaperones are essential in aiding client proteins to fold into their native structure and in maintaining cellular protein homeostasis. However, mechanistic aspects of chaperone function are still not well understood at the atomic level. We use nuclear magnetic resonance spectroscopy to elucidate the mechanism underlying client recognition by the adenosine triphosphate-independent chaperone Spy at the atomic level and derive a structural model for the chaperone-client complex. Spy interacts with its partially folded client Im7 by selective recognition of flexible, locally frustrated regions in a dynamic fashion. The interaction with Spy destabilizes a partially folded client but spatially compacts an unfolded client conformational ensemble. By increasing client backbone dynamics, the chaperone facilitates the search for the native structure. A comparison of the interaction of Im7 with two other chaperones suggests that the underlying principle of recognizing frustrated segments is of a fundamental nature.
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Alford, Brian D., and Onn Brandman. "Quantification of Hsp90 availability reveals differential coupling to the heat shock response." Journal of Cell Biology 217, no. 11 (August 21, 2018): 3809–16. http://dx.doi.org/10.1083/jcb.201803127.
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The heat shock response (HSR) is a protective gene expression program that is activated by conditions that cause proteotoxic stress. While it has been suggested that the availability of free chaperones regulates the HSR, chaperone availability and the HSR have never been precisely quantified in tandem under stress conditions. Thus, how the availability of chaperones changes in stress conditions and the extent to which these changes drive the HSR are unknown. In this study, we quantified Hsp90 chaperone availability and the HSR under multiple stressors. We show that Hsp90-dependent and -independent pathways both regulate the HSR, and the contribution of each pathway varies greatly depending on the stressor. Moreover, stressors that regulate the HSR independently of Hsp90 availability do so through the Hsp70 chaperone. Thus, the HSR responds to diverse defects in protein quality by monitoring the state of multiple chaperone systems independently.
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Gupta, Radhey S. "Microtubules, mitochondria, and molecular chaperones: a new hypothesis for in vivo assembly of microtubules." Biochemistry and Cell Biology 68, no. 12 (December 1, 1990): 1352–63. http://dx.doi.org/10.1139/o90-198.
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In Chinese hamster ovary cells, a number of independent mutants selected for resistance to antimitotic drugs have been found to be specifically altered in two major cellular proteins, designated P1 (relative mass (Mr) ≈ 60–63 kilodaltons (kDa)) and P2 (Mr ≈ 69–70 kDa), which appeared microtubule related by a number of genetic and biochemical criteria. Antibodies to P1 have been found to bind specifically to mitochondria that showed specific association with microtubules in interphase cells. Biochemical and cDNA sequence studies on P1 showed that this protein, which is localized in the matrix compartment, is the mammalian homolog of the highly conserved chaperonin family of proteins (other members include the GroEL protein of Escherichia coli, the 60-kDa heat-shock protein of yeast, and the rubisco subunit binding protein of plant chloroplasts). The chaperonin proteins in various systems play a transient but essential molecular chaperone role in the proper folding of polypeptide chains and their assembly into oligomeric protein complexes. Our studies on P2 protein established that it corresponds to the constitutive form of the major 70-kDa heat-shock protein of mammalian cells (i.e., hsc70), which also acts as a molecular chaperone in the intracellular transport of nascent proteins to organelles such as mitochondria and endoplasmic reticulum. To account for the above, as well as a number of other observations (e.g., binding of fluorescent-labeled antimitotic drugs to mitochondria, association of tubulin with mitochondria as well as other membranes, and high affinity binding of antimitotic drugs to free tubulin but not to assembled microtubules), a new model for the in vivo assembly of interphase microtubules is proposed. The model ascribes a central role to the mitochondrially localized chaperonin (i.e., P1) protein in the intracellular formation of tubulin dimers and in their addition to the growth sites in microtubules. The proposed model also explains a number of other observations related to microtubule assembly in the literature.Key words: microtubule assembly, mitochondria, molecular chaperones, heat-shock proteins, antimitotic drugs.
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Kovacs, Denes, and Peter Tompa. "Diverse functional manifestations of intrinsic structural disorder in molecular chaperones." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 963–68. http://dx.doi.org/10.1042/bst20120108.
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IDPs (intrinsically disordered proteins) represent a unique class of proteins which show diverse molecular mechanisms in key biological functions. The aim of the present mini-review is to summarize IDP chaperones that have increasingly been studied in the last few years, by focusing on the role of intrinsic disorder in their molecular mechanism. Disordered regions in both globular and disordered chaperones are often involved directly in chaperone action, either by modulating activity or through direct involvement in substrate identification and binding. They might also be responsible for the subcellular localization of the protein. In outlining the state of the art, we survey known IDP chaperones discussing the following points: (i) globular chaperones that have an experimentally proven functional disordered region(s), (ii) chaperones that are completely disordered along their entire length, and (iii) the possible mechanisms of action of disordered chaperones. Through all of these details, we chart out how far the field has progressed, only to emphasize the long road ahead before the chaperone function can be firmly established as part of the physiological mechanistic arsenal of the emerging group of IDPs.
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Maillard, Julien, Pierre Genevaux, and Christof Holliger. "Redundancy and specificity of multiple trigger factor chaperones in Desulfitobacteria." Microbiology 157, no. 8 (August 1, 2011): 2410–21. http://dx.doi.org/10.1099/mic.0.050880-0.
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The ribosome-bound trigger factor (TF) chaperone assists folding of newly synthesized polypeptides and participates in the assembly of macromolecular complexes. In the present study we showed that multiple distinct TF paralogues are present in genomes of Desulfitobacteria, a bacterial genus known for its ability to grow using organohalide respiration. Two full-length TF chaperones and at least one truncated TF (lacking the N-terminal ribosome-binding domain) were identified, the latter being systematically linked to clusters of reductive dehalogenase genes encoding the key enzymes in organohalide respiration. Using a well-characterized heterologous chaperone-deficient Escherichia coli strain lacking both TF and DnaK chaperones, we demonstrated that all three TF chaperones were functional in vivo, as judged by their ability to partially suppress bacterial growth defects and protein aggregation in the absence of both major E. coli chaperones. Next, we found that the N-terminal truncated TF-like protein PceT functions as a dedicated chaperone for the cognate reductive dehalogenase PceA by solubilizing and stabilizing it in the heterologous system. Finally, we showed that PceT specifically interacts with the twin-arginine signal peptide of PceA. Taken together, our data define PceT (and more generally the new RdhT family) as a class of TF-like chaperones involved in the maturation of proteins secreted by the twin-arginine translocation pathway.
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Rogstad, Karen E. "Chaperones: protecting the patient or protecting the doctor?" Sexual Health 4, no. 2 (2007): 85. http://dx.doi.org/10.1071/sh07022.
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The routine use of chaperones during medical examinations, including intimate examinations, is variable. Practice varies between countries and also within them. Use of a chaperone may protect patients from sexual abuse by medical or nursing practitioners. An appropriate chaperone may also protect healthcare practitioners from false accusations. This article considers issues surrounding the use of chaperones and suggests a chaperoning policy for sexual health clinics, while acknowledging that it may not be appropriate or acceptable to all patients or medical staff, or for different parts of the world.
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Huang, Yan, Yaxin Dai, and Zheng Zhou. "Mechanistic and structural insights into histone H2A–H2B chaperone in chromatin regulation." Biochemical Journal 477, no. 17 (September 17, 2020): 3367–86. http://dx.doi.org/10.1042/bcj20190852.
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Histone chaperones include a wide variety of proteins which associate with histones and regulate chromatin structure. The classic H2A–H2B type of histone chaperones, and the chromatin remodeling complex components possessing H2A–H2B chaperone activity, show a broad range of structures and functions. Rapid progress in the structural and functional study of H2A–H2B chaperones extends our knowledge about the epigenetic regulation of chromatin. In this review, we summarize the most recent advances in the understanding of the structure and function of H2A–H2B chaperones that interact with either canonical or variant H2A–H2B dimers. We discuss the current knowledge of the H2A–H2B chaperones, which present no preference for canonical and variant H2A–H2B dimers, describing how they interact with H2A–H2B to fulfill their functions. We also review recent advances of H2A variant-specific chaperones, demarcating how they achieve specific recognition for histone variant H2A.Z and how these interactions regulate chromatin structure by nucleosome editing. We highlight the universal mechanism underlying H2A–H2B dimers recognition by a large variety of histone chaperones. These findings will shed insight into the biological impacts of histone chaperone, chromatin remodeling complex, and histone variants in chromatin regulation.
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Alberti, Giusi, Letizia Paladino, Alessandra Maria Vitale, Celeste Caruso Bavisotto, Everly Conway de Macario, Claudia Campanella, Alberto J. L. Macario, and Antonella Marino Gammazza. "Functions and Therapeutic Potential of Extracellular Hsp60, Hsp70, and Hsp90 in Neuroinflammatory Disorders." Applied Sciences 11, no. 2 (January 14, 2021): 736. http://dx.doi.org/10.3390/app11020736.
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Neuroinflammation is implicated in central nervous system (CNS) diseases, but the molecular mechanisms involved are poorly understood. Progress may be accelerated by developing a comprehensive view of the pathogenesis of CNS disorders, including the immune and the chaperone systems (IS and CS). The latter consists of the molecular chaperones; cochaperones; and chaperone cofactors, interactors, and receptors of an organism and its main collaborators in maintaining protein homeostasis (canonical function) are the ubiquitin–proteasome system and chaperone-mediated autophagy. The CS has also noncanonical functions, for instance, modulation of the IS with induction of proinflammatory cytokines. This deserves investigation because it may be at the core of neuroinflammation, and elucidation of its mechanism will open roads toward developing efficacious treatments centered on molecular chaperones (i.e., chaperonotherapy). Here, we discuss information available on the role of three members of the CS—heat shock protein (Hsp)60, Hsp70, and Hsp90—in IS modulation and neuroinflammation. These three chaperones occur intra- and extracellularly, with the latter being the most likely involved in neuroinflammation because they can interact with the IS. We discuss some of the interactions, their consequences, and the molecules involved but many aspects are still incompletely elucidated, and we hope that this review will encourage research based on the data presented to pave the way for the development of chaperonotherapy. This may consist of blocking a chaperone that promotes destructive neuroinflammation or replacing or boosting a defective chaperone with cytoprotective activity against neurodegeneration.
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Baber, James A., Stephen C. Davies, and Linda S. Dayan. "An extra pair of eyes: do patients want a chaperone when having an anogenital examination?" Sexual Health 4, no. 2 (2007): 89. http://dx.doi.org/10.1071/sh06073.
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Background: Anogenital examinations can be embarrassing for patients and can leave clinicians open to accusations of professional misconduct. Little is known about the attitudes of patients in Australia towards the use of chaperones. Methods: In 2006, we surveyed 480 patients attending two sexual health clinics in northern Sydney. Our aim was to determine their attitudes towards the use of chaperones for anogenital examinations. Results: Of the 480, 58% were male and 42% female. Most women (64%) preferred a female examining clinician, whereas most men (68%) had no preference for gender of the examining clinician (P < 0.0001). While 32% of women wanted a chaperone if being examined by a male, 29% did not. Only 4% of women wanted a chaperone when being examined by a female. Only 1% of men wanted a chaperone irrespective of the sex of the examining clinician. Independent predictors of women wanting a chaperone with a male clinician were preference for a female clinician (OR 6.59, 2.48–17.5; P < 0.001) and preference for a female chaperone (OR 4.02, 1.44–11.2; P = 0.008). The majority of participants felt that they should be involved in the decision to have a chaperone. Conclusions: Although a substantial minority of women want a chaperone when being examined by a male, a similar proportion do not want a chaperone. If a woman requests a female clinician, she should be offered a chaperone if there is only a male examiner available. Further study is required to determine why some women want a chaperone and how to distinguish them from other women.
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Mikhaylova, Valeriya V., Tatiana B. Eronina, Natalia A. Chebotareva, Vladimir V. Shubin, Daria I. Kalacheva, and Boris I. Kurganov. "Effect of Arginine on Chaperone-Like Activity of HspB6 and Monomeric 14-3-3ζ." International Journal of Molecular Sciences 21, no. 6 (March 16, 2020): 2039. http://dx.doi.org/10.3390/ijms21062039.
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The effect of protein chaperones HspB6 and the monomeric form of the protein 14-3-3ζ (14-3-3ζm) on a test system based on thermal aggregation of UV-irradiated glycogen phosphorylase b (UV-Phb) at 37 °C and a constant ionic strength (0.15 M) was studied using dynamic light scattering. A significant increase in the anti-aggregation activity of HspB6 and 14-3-3ζm was demonstrated in the presence of 0.1 M arginine (Arg). To compare the effects of these chaperones on UV-Phb aggregation, the values of initial stoichiometry of the chaperone–target protein complex (S0) were used. The analysis of the S0 values shows that in the presence of Arg fewer chaperone subunits are needed to completely prevent aggregation of the UV-Phb subunit. The changes in the structures of HspB6 and 14-3-3ζm induced by binding of Arg were evaluated by the fluorescence spectroscopy and differential scanning calorimetry. It was suggested that Arg caused conformational changes in chaperone molecules, which led to a decrease in the thermal stability of protein chaperones and their destabilization.
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Santra, Mantu, Daniel W. Farrell, and Ken A. Dill. "Bacterial proteostasis balances energy and chaperone utilization efficiently." Proceedings of the National Academy of Sciences 114, no. 13 (March 14, 2017): E2654—E2661. http://dx.doi.org/10.1073/pnas.1620646114.
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Chaperones are protein complexes that help to fold and disaggregate a cell’s proteins. It is not understood how four major chaperone systems of Escherichia coli work together in proteostasis: the recognition, sorting, folding, and disaggregating of the cell’s many different proteins. Here, we model this machine. We combine extensive data on chaperoning, folding, and aggregation rates with expression levels of proteins and chaperones measured at different growth rates. We find that the proteostasis machine recognizes and sorts a client protein based on two biophysical properties of the client’s misfolded state (M state): its stability and its kinetic accessibility from its unfolded state (U state). The machine is energy-efficient (the sickest proteins use the most ATP-expensive chaperones), comprehensive (it can handle any type of protein), and economical (the chaperone concentrations are just high enough to keep the whole proteome folded and disaggregated but no higher). The cell needs higher chaperone levels in two situations: fast growth (when protein production rates are high) and very slow growth (to mitigate the effects of protein degradation). This type of model complements experimental knowledge by showing how the various chaperones work together to achieve the broad folding and disaggregation needs of the cell.
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Newton, Danielle C., Christopher K. Fairley, Richard Teague, Basil Donovan, Francis J. Bowden, Jade Bilardi, Marian Pitts, and Marcus Y. Chen. "Australian sexual health practitioners' use of chaperones for genital examinations: a survey of attitudes and practice." Sexual Health 4, no. 2 (2007): 95. http://dx.doi.org/10.1071/sh07025.
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Objectives: To examine the current practice and attitudes of Australian sexual health practitioners towards the use of chaperones for genital examinations. Methods: In July 2006, an anonymous, self-completed questionnaire was mailed to members of the Australasian Chapter of Sexual Health Medicine. Results: Of the 166 questionnaires sent to practitioners, 110 (66%) were returned completed. Of the 110 respondents, only 9% and 19% reported that their clinic routinely provided chaperones for all male and female genital examinations, respectively. Among practitioners whose services did not offer chaperones routinely, chaperones were offered with a mean frequency of 19% for female examinations and 8% for male examinations (P = 0.01). Compared to female practitioners, significantly more male practitioners thought a chaperone was important for medico-legal purposes when examining females (72% v. 53%, P < 0.05). Compared to male practitioners, significantly more female practitioners thought a chaperone was sometimes important for patient support when examining male patients (52% v. 26%, P < 0.001). Only 39% (n = 18) of male practitioners and 36% (n = 23) of female practitioners felt that resources spent on chaperones were justified by the benefits they provided. Conclusions: Despite only a minority of practitioners offering chaperones to patients or using them during examinations, many feel they are important for medico-legal reasons and as support for the patient. Best practice may be for services to routinely offer a chaperone and record instances where an offer is declined. This provides patients with choice and practitioners with some level of protection.
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Macario, Alberto J. L., and Everly Conway de Macario. "The Archaeal Molecular Chaperone Machine: Peculiarities and Paradoxes." Genetics 152, no. 4 (August 1, 1999): 1277–83. http://dx.doi.org/10.1093/genetics/152.4.1277.
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Abstract A major finding within the field of archaea and molecular chaperones has been the demonstration that, while some species have the stress (heat-shock) gene hsp70(dnaK), others do not. This gene encodes Hsp70(DnaK), an essential molecular chaperone in bacteria and eukaryotes. Due to the physiological importance and the high degree of conservation of this protein, its absence in archaeal organisms has raised intriguing questions pertaining to the evolution of the chaperone machine as a whole and that of its components in particular, namely, Hsp70(DnaK), Hsp40(DnaJ), and GrpE. Another archaeal paradox is that the proteins coded by these genes are very similar to bacterial homologs, as if the genes had been received via lateral transfer from bacteria, whereas the upstream flanking regions have no bacterial markers, but instead have typical archaeal promoters, which are like those of eukaryotes. Furthermore, the chaperonin system in all archaea studied to the present, including those that possess a bacterial-like chaperone machine, is similar to that of the eukaryotic-cell cytosol. Thus, two chaperoning systems that are designed to interact with a compatible partner, e.g., the bacterial chaperone machine physiologically interacts with the bacterial but not with the eucaryal chaperonins, coexist in archaeal cells in spite of their apparent functional incompatibility. It is difficult to understand how these hybrid characteristics of the archaeal chaperoning system became established and work, if one bears in mind the classical ideas learned from studying bacteria and eukaryotes. No doubt, archaea are intriguing organisms that offer an opportunity to find novel molecules and mechanisms that will, most likely, enhance our understanding of the stress response and the protein folding and refolding processes in the three phylogenetic domains.
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Ferrer, Manuel, Tatyana N. Chernikova, Kenneth N. Timmis, and Peter N. Golyshin. "Expression of a Temperature-Sensitive Esterase in a Novel Chaperone-Based Escherichia coli Strain." Applied and Environmental Microbiology 70, no. 8 (August 2004): 4499–504. http://dx.doi.org/10.1128/aem.70.8.4499-4504.2004.
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ABSTRACT A new principle for expression of heat-sensitive recombinant proteins in Escherichia coli at temperatures close to 4°C was experimentally evaluated. This principle was based on simultaneous expression of the target protein with chaperones (Cpn60 and Cpn10) from a psychrophilic bacterium, Oleispira antarctica RB8T, that allow E. coli to grow at high rates at 4°C (maximum growth rate, 0.28 h−1) (M. Ferrer, T. N. Chernikova, M. Yakimov, P. N. Golyshin, and K. N. Timmis, Nat. Biotechnol. 21:1266-1267, 2003). The expression of a temperature-sensitive esterase in this host at 4 to 10°C yielded enzyme specific activity that was 180-fold higher than the activity purified from the non-chaperonin-producing E. coli strain grown at 37°C (32,380 versus 190 μmol min−1 g−1). We present evidence that the increased specific activity was not due to the low growth temperature per se but was due to the fact that low temperature was beneficial to folding, with or without chaperones. This is the first report of successful use of a chaperone-based E. coli strain to express heat-labile recombinant proteins at temperatures below the theoretical minimum growth temperature of a common E. coli strain (7.5°C).
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Large, Andrew T., Martin D. Goldberg, and Peter A. Lund. "Chaperones and protein folding in the archaea." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 46–51. http://dx.doi.org/10.1042/bst0370046.
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A survey of archaeal genomes for the presence of homologues of bacterial and eukaryotic chaperones reveals several interesting features. All archaea contain chaperonins, also known as Hsp60s (where Hsp is heat-shock protein). These are more similar to the type II chaperonins found in the eukaryotic cytosol than to the type I chaperonins found in bacteria, mitochondria and chloroplasts, although some archaea also contain type I chaperonin homologues, presumably acquired by horizontal gene transfer. Most archaea contain several genes for these proteins. Our studies on the type II chaperonins of the genetically tractable archaeon Haloferax volcanii have shown that only one of the three genes has to be present for the organisms to grow, but that there is some evidence for functional specialization between the different chaperonin proteins. All archaea also possess genes for prefoldin proteins and for small heat-shock proteins, but they generally lack genes for Hsp90 and Hsp100 homologues. Genes for Hsp70 (DnaK) and Hsp40 (DnaJ) homologues are only found in a subset of archaea. Thus chaperone-assisted protein folding in archaea is likely to display some unique features when compared with that in eukaryotes and bacteria, and there may be important differences in the process between euryarchaea and crenarchaea.
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Gierasch, Lila M. "Molecular Chaperones: Panning for chaperone-binding peptides." Current Biology 4, no. 2 (February 1994): 173–74. http://dx.doi.org/10.1016/s0960-9822(94)00042-4.
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Fink, Anthony L. "Chaperone-Mediated Protein Folding." Physiological Reviews 79, no. 2 (April 1, 1999): 425–49. http://dx.doi.org/10.1152/physrev.1999.79.2.425.
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The folding of most newly synthesized proteins in the cell requires the interaction of a variety of protein cofactors known as molecular chaperones. These molecules recognize and bind to nascent polypeptide chains and partially folded intermediates of proteins, preventing their aggregation and misfolding. There are several families of chaperones; those most involved in protein folding are the 40-kDa heat shock protein (HSP40; DnaJ), 60-kDa heat shock protein (HSP60; GroEL), and 70-kDa heat shock protein (HSP70; DnaK) families. The availability of high-resolution structures has facilitated a more detailed understanding of the complex chaperone machinery and mechanisms, including the ATP-dependent reaction cycles of the GroEL and HSP70 chaperones. For both of these chaperones, the binding of ATP triggers a critical conformational change leading to release of the bound substrate protein. Whereas the main role of the HSP70/HSP40 chaperone system is to minimize aggregation of newly synthesized proteins, the HSP60 chaperones also facilitate the actual folding process by providing a secluded environment for individual folding molecules and may also promote the unfolding and refolding of misfolded intermediates.
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Griessl, Martin H., Isabel Jungkunz, Uwe Sonnewald, and Yves A. Muller. "Purification, crystallization and preliminary X-ray diffraction analysis of the Hsp40 protein CPIP1 fromNicotiana tabacum." Acta Crystallographica Section F Structural Biology and Crystallization Communications 68, no. 2 (January 27, 2012): 236–39. http://dx.doi.org/10.1107/s1744309111055928.
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Chaperones promote many different molecular processes, including the folding, targeting and degradation of proteins. The best-studied chaperone system consists of the Hsp70s and their co-chaperones the Hsp40s. Chaperone function can be hijacked by viruses in plants.Potato virus Yinteractsviaits coat protein with an Hsp40 fromNicotiana tabacum, referred to as NtCPIP1, in order to regulate replication. To understand the molecular determinants of this mechanism, different variants of NtCPIP1 were expressed, purified and crystallized. While crystals of wild-type NtCPIP1 diffracted to 8.0 Å resolution, the deletion mutant NtCPIP1-Δ(1:127) crystallized in space groupP21212 and diffracted to 2.4 Å resolution.