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PubMed2004

Evolution of assisted protein folding: the distribution of the main chaperoning systems within the phylogenetic domain archaea.

Newly made proteins must achieve a functional shape, the native configuration, before they can play their physiological roles in the cell. Proteins must also travel to the locale (e.g., the mitochondrion) in the cell where their functions are required. In these processes of folding into the native configuration and translocation to the place of work, proteins may be assisted by molecules called molecular chaperones. Stressors can unfold (denature) proteins, and genetic defects can cause misfolding and, in addition, both abnormalities can lead to polypeptide aggregation. Chaperones play a role in assisting refolding of partially denatured or misfolded proteins, thus preventing aggregation. Clearly, molecular chaperones are key cell components under normal, physiological circumstances, as well as in potentially harmful situations resulting from environmental or inherited factors. Hence, molecular chaperones constitute attractive targets for a variety of efforts aiming at improving the cell's performance, particularly under stress, to prevent disease, or at least to slow down its progression and to contain the deleterious effects of stress. In our efforts in this direction, we have undertaken to investigate the chaperoning systems of cells belonging to the phylogenetic domain Archaea. The findings reported here pertain to the distribution of the molecular chaperone machine, the chaperonins, and the prefoldins, among archaea. The genes hsp70(dnaK), hsp40(dnaJ), and grpE encoding the components of the molecular chaperone machine were present only in some archeaeal species: this contrasts with bacteria and eucarya, which do have the genes with no known exception. The group I, or bacterial, chaperonin-genes groEL and groES occured in the genomes of Methanosarcina species but were not found in any of the other archaea whose genomes have been sequenced. While all the archaea studied had between one and three chaperonins of group II (thermosome subunits), Methanosarcina acetivorans was exceptional since it had five of these chaperonins. This is the largest number of group II chaperonins ever found in a prokaryote. Furthermore, two of the M. acetivorans chaperonins were different from, albeit related to, the other known archaeal and eucaryal chaperonins of group II. Prefoldins were found in all archaea examined. Overall, the results provide clues to the evolution of the chaperoning systems, which must have played a critical role in survival since life started. Also, the data suggest new avenues of research for elucidating the evolution of assisted protein folding and for uncovering roles and interactions not yet described for these molecules.

Archaea↗

PubMed2005

Arginine hydrochloride enhances the dynamics of subunit assembly and the chaperone-like activity of alpha-crystallin.

PURPOSE: Alpha-crystallin, a major eye lens protein, bears homology with small heat shock proteins (sHsps) and exhibits molecular chaperone-like activity. Structural perturbation by temperature or low concentrations of denaturants leads to enhancement of its chaperone-like activity. We have earlier demonstrated similar enhancement of chaperone-like activity using biologically compatible solutes such as arginine hydrochloride and aminoguanidine. The purpose of the present study is to get an insight into the mechanism of the arginine induced enhancement of chaperone-like activity of alpha-crystallin. METHODS: The effect of arginine hydrochloride on the chaperone-like activity of alpha-crystallin at 25 degrees C was studied using DTT induced aggregation of insulin as a model system. Changes in the accessibility of the thiol group near the end of the alpha-crystallin domain in the absence and the presence of arginine hydrochloride were studied using dithiobisnitrobenzoic acid. Fluorescence resonance energy transfer studies were performed to investigate changes in the dynamics of the subunit assembly. Urea induced denaturation studies of alpha-crystallin were carried out to investigate structural destabilization of alpha-crystallin, if any, in the presence of arginine hydrochloride. RESULTS: Arginine hydrochloride increases the chaperone-like activity of alpha-crystallin several fold towards DTT induced aggregation of insulin at room temperature. Our study shows that both the extent and the rate of accessibility of the thiol group are increased in the presence of arginine. Fluorescence resonance energy transfer experiments show that arginine hydrochloride significantly increases the subunit exchange between the oligomers of alpha-crystallin. Arginine induced structural perturbation and loosening of subunit assembly of alpha-crystallin leads to overall destabilization of the protein as reflected by the urea denaturation study. CONCLUSIONS: Arginine perturbs the tertiary and quaternary structure of alpha-crystallin and enhances the dynamics of the subunit assembly leading to enhanced chaperone-like activity. Thus, in addition to size, surface hydrophobicity, and charge distribution, the dynamics of the subunit assembly appears to be one of the critical factors that can modulate the chaperone activity.

Animals↗

PubMed2006

Carnosine inhibits modifications and decreased molecular chaperone activity of lens alpha-crystallin induced by ribose and fructose 6-phosphate.

PURPOSE: Alpha-crystallin, a major structural protein in the lens, prevents heat- and oxidative stress-induced aggregation of proteins and inactivation of enzymes by acting as a molecular chaperone. Modification of alpha-crystallin by some posttranslational modifications results in conformational changes and decreases in chaperone activity, which may contribute to cataractogenesis in vivo. Carnosine (beta-alanyl-L-histidine), an endogenous histidine dipeptide, prevents protein modifications including glycation and oxidation. The purpose of this study was to further explore whether carnosine can protect alpha-crystallin against glycation by a sugar and a sugar phosphate, and in particular to find whether it can protect against its decreased chaperone activity. Additionally, we investigated whether carnosine could directly react with a sugar and a sugar phosphate. METHODS: Bovine lens alphaL-crystallin was separated by size-exclusion chromatography on a Sephacryl S-300 HR column. alphaL-crystallin was incubated with different concentrations of fructose 6-phosphate (F6P) and ribose with or without carnosine for different times. The chaperone activity of alphaL-crystallin was monitored using the prevention of thermal aggregation of betaL-crystallin. The modified alphaL-crystallin was examined by SDS-PAGE and fluorescence measurements. The absorbance spectra of solutions of carnosine and sugars were investigated. RESULTS: Carnosine inhibited the crosslinking of alphaL-crystallin induced by F6P and ribose in a dose- and time-dependent manner. It protected alphaL-crystallin against its decreased chaperone activity induced by 100 mM F6P during four days incubation, but not against ribose-induced change. Control alphaL-crystallin gave 96% protection against aggregation of betaL-crystallin after four days incubation, but only 85% protection was achieved in the presence of F6P, rising to 96% (p=0.0004) in the presence of carnosine. After more extensive modification by sugar and a sugar phosphate, there was no significant protective effect of carnosine on alphaL-crystallin cross-linking or chaperone activity. The tryptophan fluorescence of modified alphaL-crystallin was remarkably decreased in the presence of F6P and ribose. However, the decrease was less when 50 mM carnosine was present during eight days incubation with F6P. Carnosine did not maintain the fluorescence when ribose was used. The nontryptophan fluorescence was increased with a shift to longer wavelengths in a time-dependent manner. Carnosine readily reacted with F6P and ribose thereby inhibiting glycation-mediated protein modification as revealed electrophoretically. The increased absorbance was time-dependent, suggesting adducts may be formed between F6P, ribose, and carnosine. CONCLUSIONS: This is the first report showing that carnosine can protect the chaperone activity of alpha-crystallin. This chaperone may protect against cataractous changes. In addition to demonstrating the effects of carnosine on prevention crosslinking, our studies also bring out important evidence that carnosine reacts with F6P and ribose, which suggests carnosine's potential as a possible nontoxic modulator of diabetic complications.

Animals↗

PubMed1996

Molecular basis of two subfamilies of immunoglobulin-like chaperones.

The initial encounter of a microbial pathogen with the host often involves the recognition of host receptors by different kinds of bacterial adhesive organelles called pili, fimbriae, fibrillae or afimbrial adhesins. The development of over 26 of these architecturally diverse adhesive organelles in various Gram-negative pathogens depends on periplasmic chaperones that are comprised of two immunoglobulin-like domains. All of the chaperones possess a highly conserved sheet in domain 1 and a conserved interdomain hydrogen-bonding network. Chaperone-subunit complex formation depends on the anchoring of the carboxylate group of the subunit into the conserved crevice of the chaperone cleft and the subsequent positioning of the COOH terminus of subunits along the exposed edge of the conserved sheet of the chaperone. We discovered that the chaperones can be divided into two distinct subfamilies based upon conserved structural differences that occur in the conserved sheet. Interestingly, a subdivision of the chaperones based upon whether they assemble rod-like pili or non-pilus organelles that have an atypical morphology defines the same two subgroups. The molecular dissection of the two chaperone subfamilies and the adhesive fibers that they assemble has advanced our understanding of the development of virulence-associated organelles in pathogenic bacteria.

Amino Acid Sequence↗

PubMed2005

Substrate transfer from the chaperone Hsp70 to Hsp90.

Hsp90 is an essential chaperone protein in the cytosol of eukaryotic cells. It cooperates with the chaperone Hsp70 in defined complexes mediated by the adaptor protein Hop (Sti1 in yeast). These Hsp70/Hsp90 chaperone complexes play a major role in the folding and maturation of key regulatory proteins in eukaryotes. Understanding how non-native client proteins are transferred from one chaperone to the other in these complexes is of central importance. Here, we analyzed the molecular mechanism of this reaction using luciferase as a substrate protein. Our experiments define a pathway for luciferase folding in the Hsp70/Hsp90 chaperone system. They demonstrate that Hsp70 is a potent capture device for unfolded protein while Hsp90 is not very efficient in this reaction. When Hsp90 is absent, in contrast to the in vivo situation, Hsp70 together with the two effector proteins Ydj1 and Sti1 exhibits chaperone activity towards luciferase. In the presence of the complete chaperone system, Hsp90 exhibits a specific positive effect only in the presence of Ydj1. If this factor is absent, the transferred luciferase is trapped on Hsp90 in an inactive conformation. Interestingly, identical results were observed for the yeast and the human chaperone systems although the regulatory function of human Hop is completely different from that of yeast Sti1.

Adenosine Triphosphatases↗

PubMed1991

Immunoglobulin-like PapD chaperone caps and uncaps interactive surfaces of nascently translocated pilus subunits.

Molecular chaperones are found in the cytoplasm of bacteria and in various cellular compartments in eukaryotes to maintain proteins in nonnative conformations that permit their secretion across membranes or assembly into oligomeric structures. Virtually nothing, however, has been reported about a similar requirement for molecular chaperones in the periplasm of Gram-negative bacteria. We used the well-characterized P pilus biogenesis system in Escherichia coli as a model to elucidate the mechanism of action of a periplasmic chaperone, PapD, which is specifically required for P pilus biogenesis. PapD probably associates with at least six P pilus subunits after their secretion across the cytoplasmic membrane, but PapD is not incorporated into the pilus. We used purified periplasmic complex that PapD forms with the PapG adhesin to investigate the function of interactions between the chaperone and its targets. We demonstrated that PapD binds to PapG to form a stable, discrete bimolecular complex and that, unlike cytoplasmic chaperones, the periplasmic PapD chaperone maintained PapG in a native-like conformation. Bound PapD in the complex was displaced by free PapD in vitro; however, the in vivo release of subunits to the nascent pilus is probably driven by an ATP-independent mechanism involving the outer membrane protein PapC. In addition, the binding of PapD to PapG in vitro prevented aggregation of PapG. We propose that the function of PapD and other periplasmic pilus chaperones is to partition newly translocated pilus subunits into assembly-competent complexes and thereby prevent nonproductive aggregation of the subunits in the periplasm. These data provide important information for understanding the mechanism of action of this general class of chaperones that function in the periplasmic space.

Adhesins, Escherichia coli↗

PubMed1998

Chaperone coexpression plasmids: differential and synergistic roles of DnaK-DnaJ-GrpE and GroEL-GroES in assisting folding of an allergen of Japanese cedar pollen, Cryj2, in Escherichia coli.

Plasmids that can be used for controlled expression of the DnaK-DnaJ-GrpE and/or GroEL-GroES chaperone team were constructed in order to facilitate assessment of the effects of these chaperone teams on folding or assembly or recombinant proteins in Escherichia coli. A typical pACYC184-based plasmid which was obtained could express the major DnaK-DnaJ-GrpE and GroEL-GroES chaperone teams from separate promoters when L-arabinose and tetracycline, respectively, were added in a dose-dependent fashion. The model protein used to determine whether this system was useful was an allergen of Japanese cedar pollen, Cryj2, which was unstable when it was produced in E. coli K-12. The effects of chaperone coexpression on the folding, aggregation, and stability of Cryj2 were examined in the wild type and in several mutant bacteria. Coexpression of the DnaK-DnaJ-GrpE and/or GroEL-GroES chaperone team at appropriate levels resulted in marked stabilization and accumulation of Cryj2 without extensive aggregation. Experiments performed with mutants that lack each of the chaperone proteins (DnaK, DnaJ, GrpE, GroEL, and GroES) or heat shock transcription factor sigma 32 revealed that both chaperone teams are critically involved in Cryj2 folding but that they are involved in distinct ways. In addition, it was observed that the two chaperone teams have synergistic roles in preventing aggregation of Cryj2 in the absence of sigma 32 at certain temperatures.

Allergens↗

PubMed1992

Patients' attitudes regarding chaperones during physical examinations.

BACKGROUND: This study was undertaken to determine the preference of patients concerning the presence of a chaperone during physical examination of the breasts, genitals, rectum, heart and lungs, or abdomen. The study was designed to quantify preference differences between male and female patients and between teenagers and adults, and to determine whether the sex of the examining physician influenced chaperone preference. METHODS: Preference survey data were obtained from 251 female subjects and 201 male subjects over the age of 13 years who visited a family practice center in a midwestern urban community. RESULTS: The majority of patients of either sex and all ages did not care if a chaperone was present. However, substantial proportions of adult women (29%) and female teenagers (46%) preferred that a chaperone be present during a breast, pelvic, or rectal examination by a male physician. Thirty-six percent of adult women and 63% of female teenagers wanted a chaperone present during a first examination of these regions. Adults of both sexes felt the nurse would be the best chaperone, whereas teenagers ranked a parent first and the nurse second. Patients indicated that they felt comfortable asking for a chaperone. CONCLUSIONS: Although most patients have no strong preference, female patients, especially female teenagers, should be given the option of having a chaperone present during an examination of the breasts, pelvis, or rectum by a male physician.

Adolescent↗

PubMed1990

The molecular chaperone concept.

Molecular chaperones are a ubiquitous family of cellular proteins which mediate the correct folding of other polypeptides, and in some cases their assembly into oligomeric structures, but which are not components of those final structures. Known chaperones do not possess steric information for protein folding but inhibit unproductive folding and assembly pathways which would otherwise act as dead-end kinetic traps and produce incorrect structures. Chaperones function by binding specifically and non-covalently to interactive protein surfaces that are exposed transiently during cellular processes such as protein synthesis, protein transport across membranes, DNA synthesis, the recycling of clathrin cages, the assembly of organellar complexes from imported subunits, and stress responses. This binding is reversed under circumstances which favour correct interactions and in some cases ATP hydrolysis is involved in this reversal. Some chaperones bind specifically to a structural feature present in a wide range of unrelated proteins that is accessible only during the early stages of folding. The nature of this structural feature is unknown, but its identification is an important goal of current research. Knowledge of chaperone function may be important for the production of proteins for biotechnological purposes since in some cases chaperones may improve the yield of functional product. It is likely that chaperone diseases exist which result from the failure of certain proteins to fold correctly due to changes in chaperone structure.

Binding Sites↗

PubMed1997

Dietary energy tissue-specifically regulates endoplasmic reticulum chaperone gene expression in the liver of mice.

A number of putative molecular chaperones seem to play essential roles in the correct folding, assembly and glycosylation of membrane and secreted proteins in the endoplasmic reticulum. We have shown that life span-extending dietary energy restriction significantly and specifically reduces GRP78 mRNA and protein by 50-75% in mice. Here, 5-mo-old female C3B10RF1 mice were given free access to food after being fed 50% less dietary energy since weaning. Hepatic GRP78 mRNA increased linearly, reaching the same level after 2 wk as was found in the liver of 20-mo-old mice with free access to food. This increase took place with no change in body weight. The mRNA levels of endoplasmic reticulum, cytosolic and mitochondrial chaperones were determined in young (7-mo-old) and old (21- or 28-mo-old) female C3B10RF1 mice. Each age group was either 50% energy restricted or was fed approximately 10% less energy than consumed by mice given free access to food. In young and old energy-restricted mice, hepatic expression of the endoplasmic reticulum chaperones ERp57 (37%), GRP170 (51%), ERp72 (43%), calreticulin (54%) and calnexin (23%) was significantly and specifically reduced. The GRP78, GRP94, GRP170, ERp57 and calnexin mRNA response to diet occurred reproducibly only in liver, and not in adipose, brain, heart, kidney, lung, muscle or small intestine. The mRNA for GRP75, a mitochondrial chaperone, HSC70, a cytoplasmic chaperone, protein disulfide isomerase, an endoplasmic reticulum chaperone, and C/EBPalpha, a transcription factor, was not regulated. Hepatic C/EBPbeta was 15% higher in old energy-restricted mice. Thus the expression of nearly all endoplasmic reticulum chaperones responded rapidly and specifically to dietary energy in mice.

Aging↗

PubMed1996

Supervising the fold: functional principles of molecular chaperones.

Molecular chaperones are a set of conserved protein families that share the remarkable ability to recognize and selectively bind nonnative proteins under physiological and stress conditions. Thus, they prevent irreversible aggregation reactions and keep proteins on the productive folding pathway. Evidence suggests that the cell has developed several functionally distinct chaperone families to support protein folding. The importance of molecular chaperones under stress conditions is highlighted by the finding that all the major heat shock protein families (Hsp104, Hsp90, Hsp70, Hsp60/GroEL, and small Hsps) suppress irreversible unfolding reactions. Under heat shock, only the increased expression of a repertoire of different chaperones seems to convey thermotolerance and guarantee survival. The molecular mechanism by which chaperones in general influence protein folding processes is still far from clear. However, significant progress has been achieved in understanding some of the partial reactions of the chaperone folding cycles and in functionally differentiating between the different chaperone families.

Bacterial Proteins↗

PubMed2005

Chaperoning prions: the cellular machinery for propagating an infectious protein?

Newly made polypeptide chains require the help of molecular chaperones not only to rapidly reach their final three-dimensional forms, but also to unfold and then correctly refold them back to their biologically active form should they misfold. Most prions are an unusual type of protein that can exist in one of two stable conformations, one of which leads to formation of an infectious alternatively folded form. Studies in Baker's yeast (Saccharomyces cerevisiae) have revealed that prions can exploit the molecular chaperone machinery in the cell in order to ensure stable propagation of the infectious, aggregation-prone form. The disaggregation of yeast prion aggregates by molecular chaperones generates forms of the prion protein that can seed the protein polymerisation that underlies the prion propagation cycle. In this article, we review what we have learnt about the role of molecular chaperones in yeast prion propagation, describe a model that can explain the role of various classes of molecular chaperones and their co-chaperones, and speculate on the possible involvement of chaperones in the propagation of mammalian prions.

Cytosol↗

PubMed1996

Conformational states bound by the molecular chaperones GroEL and secB: a hidden unfolding (annealing) activity.

We have analysed the conformational states of barnase that are bound by the molecular chaperones GroEL and SecB. Line broadening in the NMR spectra of barnase in the presence of chaperone indicates binding of the native state of barnase to both GroEL and SecB, with a dissociation constant of > 3 x 10(-4) M for the GroEL-native barnase complex. GroEL and SecB catalyse the hydrogen-deuterium exchange of amide proteins of barnase that require global unfolding for exchange to occur, indicating that both chaperones bind to a fully unfolded state of barnase. Binding of the denatured state was also detected by a reversible lowering of the melting temperature of barnase in the presence of chaperone. The dissociation constant of the complex between denatured barnase and either chaperone is 5 x 10(-8) M. The chaperone-bound fully unfolded state is a minor conformation that would not be seen by direct observation under physiological conditions, as the folding intermediate of barnase is the most populated state in the complex. The rate-limiting step for exchange of buried amide protons of bound barnase is the unfolding of the folding intermediate, which is retarded > 2000-fold in the complex with GroEL. The reverse refolding step is retarded > 1000-fold by GroEL leading to an EX1 mechanism for exchange. In contrast, unfolding of native barnase is catalysed by > 1000-fold. Thus, molecular chaperones GroEL and SecB have the potential to act in vivo and in vitro as: (1) a folding/transport-scaffold to prevent aggregation of partially folded states by binding; (2) as an annealing-machine to generate continuous unfolding of misfolded states until a low-affinity state is formed; and (3) as an unfoldase to catalyse unfolding of the misfolded states.

Amides↗

PubMed2002

Affinity purification and characterization of the Escherichia coli molecular chaperones.

The molecular chaperones are a group of proteins that are effective in vitro and in vivo folding aids and show a well-documented affinity for proteins lacking tertiary structure. The molecular chaperones were induced from lon(-) Escherichia coli mutants, affinity purified with an immobilized beta-casein column, and assayed for refolding activity with thermally and chemically denatured carbonic anhydrase B (CAB). Chaperones were induced with three treatments: heat shock at 39 degrees C, heat shock 42 degrees C, and alcohol shock with 3% ethanol (v/v). Lysates were applied to an immobilized beta-casein (30 mg/g beads) column. After removing nonspecifically bound proteins with 1 M NaCl, the molecular chaperones were eluted with cold water or 1 mM Mg-ATP. The cold water and Mg-ATP eluates were analyzed by SDS-PAGE. Western analysis identified five E. coli molecular chaperones including DnaK, DnaJ, GrpE, GroEL, and GroES. The purity of eluted chaperones was 58% with cold water and 100% with Mg-ATP. Refolding denatured CAB in the presence of Mg-ATP resulted in a 97% recovery of heat-denatured CAB and a 68% recovery of chemically denatured CAB. The use of affinity matrices for the chaperone purification which are effective as in vitro folding aids will be presented.

Bacterial Proteins↗

PubMed1999

Molecular chaperones stimulate bone resorption.

Molecular chaperones, also known as heat shock proteins (hsp), are intracellular proteins found in all cells that catalyze protein folding. We have discovered that one class of bacterial molecular chaperone, the chaperonins, are potent inducers of bone resorption. To address the question of whether the osteolytic activity of the chaperonins was unique to this protein class, or was a common attribute of molecular chaperones generally, we have examined a number of bacterial and mammalian molecular chaperones for activity in the murine calvarial bone resorption assay. All the Escherichia coli molecular chaperones (groEL, groES, and dnaK) were active. The osteolytic activity of groEL was inhibited by indomethacin and the natural antagonist of interleukin-1 receptor antagonist (IL-1ra) but was unaffected by neutralization of tumor necrosis factor (TNF) or inhibition of 5-lipoxygenase. Mammalian molecular chaperones of molecular mass 27, 47, 70, and 90 kDa were also tested and, with the exception of the 47 kDa protein, all showed activity in the murine calvarial assay. Molecular chaperones appear, therefore, to have the capacity to modulate the cellular processes in bone explant cultures, resulting in resorption of the calcified matrix. The possibility that these proteins could play a role in the normal or pathological remodeling of bone is discussed.

Animals↗

PubMed2001

Molecular chaperones encoded by a reduced nucleus: the cryptomonad nucleomorph.

Molecular chaperones mediate the correct folding of nascent or denatured proteins and are found in both the organelles and cytoplasm of eukaryotic cells. Cryptomonad algae are unusual in possessing an extra cytoplasmic compartment (the periplastid space), the result of having engulfed and retained a photosynthetic eukaryote. Within the periplastid space is a diminutive nucleus (the nucleomorph) that encodes mostly genes for its own expression as well as a few needed by the plastid. Two plastid-encoded chaperones (GroEL and DnaK) and a nucleomorph-encoded chaperone (Cpn60) have been reported from the cryptomonad, Guillardia theta. Here we analyse G. theta nucleomorph genes for members of the cytosolic HSP70 and HSP90 families of molecular chaperones, a heat shock transcription factor (HSF), and all eight subunits of the group II chaperonin, CCT. These are presumably all active in the periplastid space, assisting in the maturation of polypeptides required by the cell; we propose a central role for them also in the structure and assembly of a putative relict mitotic apparatus. Curiously, none of the genes for co-chaperones of HSP70, HSP90, or CCT have been detected in the nucleomorph genome; they are either not needed or are encoded in the host nuclear genome and targeted back into the periplastid space. Endoplasmic reticulum (ER) homologs of HSP70 and HSP90 are also not present. Striking differences in the degree of conservation of the various nucleomorph-encoded molecular chaperones were observed. While the G. theta HSP70 and HSP90 homologs are well conserved, each of the eight CCT subunits (alpha, beta, gamma, delta, epsilon, eta, theta, and zeta) is remarkably divergent. Such differences are likely evidence for reduced/different functional constraints on the various molecular chaperones functioning in the periplastid space.

Amino Acid Motifs↗

PubMed2000

Stress and molecular chaperones in disease.

Stress, a common phenomenon in today's society, is suspected of playing a role in the development of disease. Stressors of various types, psychological, physical, and biological, abound. They occur in the working and social environments, in air, soil, water, food, and medicines. Stressors impact on cells directly or indirectly, cause protein denaturation, and elicit a stress response. This is mediated by stress (heat-shock) genes and proteins, among which are those named molecular chaperones because they assist other proteins to achieve and maintain a functional shape (the native configuration), and to recover it when partially lost due to stress. Denatured proteins tend to aggregate and precipitate. The same occurs with abnormal proteins due to mutations, or to failure of post-transcriptional or post-translational mechanisms. These abnormal proteins need the help of molecular chaperones as much as denatured molecules do, especially during stress. A cell with normal antistress mechanisms, including a complete and functional set of chaperones, may be able to withstand stress if its intensity is not beyond that which will cause irreversible protein damage. There is a certain threshold that normal cells have above which they cannot cope with stress. A cell with an abnormal protein that has an intrinsic tendency to misfold and aggregate is more vulnerable to stress than normal counterparts. Furthermore, these abnormal proteins may precipitate even in the absence of stress and cause diseases named proteinopathies. It is possible that stress contributes to the pathogenesis of proteinopathies by promoting protein aggregation, even in cells that possess a normal chaperoning system. Examples of proteinopathies are age-related degenerative disorders with protein deposits in various tissues, most importantly in the brain where the deposits are associated with neuronal degeneration. It is conceivable that stress enhances the progression of these diseases by facilitating protein unfolding and misfolding, which lead to aggregation and deposition. A number of reports in the last few years have described research aimed at elucidating the role of heatshock proteins, molecular chaperones in particular, in the pathogenesis of neurodegenerative disorders. The findings begin to shed light on the molecular mechanism of protein aggregation and deposition, and of the ensuing cell death. The results also begin to elucidate the role of molecular chaperones in pathogenesis. This is a fascinating area of research with great clinical implications. Although there are already several experimental models for the study of proteinopathies, others should be developed using organisms that are better known now than only a few years ago and that offer unique advantages. Use of these systems and of information available in databases from genome sequencing efforts should boost research in this field. It should be possible in the not-too-distant future to develop therapeutic and preventive means for proteinopathies based on the use of heat-shock protein and molecular chaperone genes and proteins.

Humans↗

PubMed1999

Copper chaperones: function, structure and copper-binding properties.

Copper is an absolute requirement for living systems and the intracellular trafficking of this metal to copper-dependent proteins is fundamental to normal cellular metabolism. The copper chaperones perform the dual functions of trafficking and the prevention of cytoplasmic exposure to copper ions in transit. Only a small number of copper chaperones have been identified at this time but their conservation across plant, bacterial and animal species suggests that the majority of living systems utilise these proteins for copper routing. The available data suggest that each copper-dependent protein in the cell is served by a specific copper chaperone. Although copper chaperones cannot be substituted for one another in a given cell type, copper chaperones that deliver to the same protein in different cell types appear to be functionally equivalent. The majority of the copper chaperones identified thus far have an "open-faced beta-sandwich" global fold with a conserved MXCXXC metal-binding motif. Specificity for a given copper-dependent protein appears to be mediated by the residues surrounding the copper-binding motif. Copper binds to such proteins as Cu(I) in a trigonal complex with three sulfur ligands. Only the copper chaperone specific for cytochrome-c-oxidase, Cox17, deviates from this design.

Amino Acid Sequence↗