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Current Topics in Medicinal Chemistry 2006The heat shock protein 90 (HSP90) chaperones represent some 1-2% of all cellular protein and are key players in protein quality control in cells. They are over expressed... (Review)
Review
The heat shock protein 90 (HSP90) chaperones represent some 1-2% of all cellular protein and are key players in protein quality control in cells. They are over expressed in many human cancers and the fact that many oncogenic proteins are clients has prompted much recent research on HSP90 inhibitors as new cancer therapeutics. A brief introduction is followed by a detailed review of the various classes of inhibitors, both natural product-based and synthetic, that have emerged over the last decade. The natural products geldanamycin, radicicol and novobiocin have provided the start points for new drugs in this area and their medicinal chemistry is reviewed, including the exciting recent results emerging from clinical trials using geldanamycin analogues. The detailed understanding of the binding mode of these compounds to HSP90 has been significantly enhanced by X-ray crystallography of HSP90 constructs co-crystallised with various ligands. Efforts to replace the natural product inhibitors with more drug-like synthetic compounds have mushroomed over the last 4 years. The purines and the 3,4-diarylpyrazoles have proven to be the most successful and their medicinal chemistry is reviewed with particular emphasis on structure-based design. Protein/ligand co-crystal structures have shown that conserved water molecules in the active site are a vital part of the hydrogen-bonding network established on binding both natural product and synthetic inhibitors. Medicinal chemists have used this information to develop high affinity lead compounds. Recent research provides the platform for exciting developments in the area of HSP90 inhibition over the next few years.
Topics: Animals; Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Molecular Structure; Neoplasms; Protein Binding
PubMed: 16842148
DOI: 10.2174/156802606777812004 -
Biochemistry and Cell Biology =... 1995Calnexin is an integral membrane protein of the endoplasmic reticulum (ER) that binds transiently to a wide array of newly synthesized membrane and secretory proteins.... (Review)
Review
Calnexin is an integral membrane protein of the endoplasmic reticulum (ER) that binds transiently to a wide array of newly synthesized membrane and secretory proteins. It also exhibits prolonged binding to misfolded or incompletely folded proteins. Recent studies have demonstrated that calnexin functions as a molecular chaperone to facilitate the folding and assembly of proteins in the ER. It is also a component of the quality control system that prevents proteins from progressing along the secretory pathway until they have acquired proper tertiary or quaternary structure. Most proteins that are translocated into the ER are glycosylated at Asn residues, and calnexin's interactions are almost exclusively restricted to proteins that possess this posttranslational modification. The preference for glycoproteins resides in calnexin's ability to function as a lectin with specificity for the Glc1Man9GlcNAc2 oligosaccharide, an early intermediate in the processing of Asn-linked oligosaccharides. Calnexin also has the capacity to bind to polypeptide segments of unfolded glycoproteins. Available evidence suggests that calnexin utilizes its lectin property during initial capture of a newly synthesized glycoprotein and that subsequent association (and chaperone function) is mediated through polypeptide interactions. Unlike other molecular chaperones that are soluble proteins, calnexin is an intrinsic component of the ER membrane. Its unique ability to capture unfolded glycoproteins through their large oligosaccharide moieties may have evolved as a means to overcome accessibility problems imposed by being constrained within a lipid bilayer.
Topics: Amino Acid Sequence; Animals; Calcium-Binding Proteins; Calnexin; Carbohydrate Metabolism; Humans; Molecular Chaperones; Molecular Sequence Data; Protein Folding
PubMed: 7576485
DOI: 10.1139/o95-015 -
Medicinal Research Reviews Jan 2022Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein... (Review)
Review
Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors. Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side-effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co-chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase-specific recognizer and has shown that the HSP90-CDC37-kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90-CDC37-kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90-CDC37-kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.
Topics: Cell Cycle Proteins; Chaperonins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms; Protein Binding
PubMed: 33846988
DOI: 10.1002/med.21807 -
Histochemistry and Cell Biology Sep 2020The vertebrate-specific co-chaperone Mdg1/ERdj4, which is localized in the endoplasmic reticulum, controls the folding and degradation of proteins. We characterized its...
The vertebrate-specific co-chaperone Mdg1/ERdj4, which is localized in the endoplasmic reticulum, controls the folding and degradation of proteins. We characterized its protein pattern during chick embryonic development. During early development, Mdg1/ERdj4 protein is present in mesenchymal and epithelial cells. In mesenchymal cells, it has a salt and pepper pattern. In contrast, during epithelial tissue differentiation, Mdg1/ERdj4 marks the basal and/or apical compartment of epithelial linings. The distinct protein pattern in epithelial tissue might point to its role in organizing and maintaining the epithelial structure. This could be achieved, e.g. by controlling folding and secretion of membrane-bound receptors or by inhibiting the IRE1α-Xbp1s-SNAI1/2-induced mesenchymalization. High Mdg1/ERdj4 protein levels are maintained in tissue with sustained secretory activity as in ependymal cells or enterocytes, substantiating its important role for secretion. We conclude that the transient elevation of Mdg1/ERdj4 protein levels controls the differentiation of epithelial linings while constitutive high levels are closely linked to secretory activity.
Topics: Animals; Chick Embryo; Chickens; Embryonic Development; HSP40 Heat-Shock Proteins; Immunohistochemistry; Molecular Chaperones
PubMed: 32377843
DOI: 10.1007/s00418-020-01881-x -
The Journal of Biological Chemistry Feb 2019Chaperones are a highly interactive group of proteins that function globally in many cellular processes involved in maintaining protein homeostasis. Traditional... (Review)
Review
Chaperones are a highly interactive group of proteins that function globally in many cellular processes involved in maintaining protein homeostasis. Traditional biochemical assays typically do not provide a complete view of the intricate networks through which chaperones collaborate to promote proteostasis. Recent advances in high-throughput systematic analyses of chaperone interactions have uncovered that chaperones display a remarkable cooperativity in their interactions with numerous client proteins. This cooperativity has been found to be a fundamental aspect of a properly functioning cell. Aberrant formation or improper regulation of these interactions can easily lead to disease states. Herein, we provide an overview of the use of large-scale interaction assays, whether physical (protein-protein) or genetic (epistatic), to study chaperone interaction networks. Importantly, we discuss the ongoing need for such studies to determine the mechanisms by which protein homeostasis is controlled in the cell.
Topics: Animals; Humans; Molecular Chaperones; Protein Interaction Maps; Proteostasis
PubMed: 30194284
DOI: 10.1074/jbc.TM118.002805 -
Biochimica Et Biophysica Acta Sep 2015Plastids are a class of essential plant cell organelles comprising photosynthetic chloroplasts of green tissues, starch-storing amyloplasts of roots and tubers or the... (Review)
Review
Plastids are a class of essential plant cell organelles comprising photosynthetic chloroplasts of green tissues, starch-storing amyloplasts of roots and tubers or the colorful pigment-storing chromoplasts of petals and fruits. They express a few genes encoded on their organellar genome, called plastome, but import most of their proteins from the cytosol. The import into plastids, the folding of freshly-translated or imported proteins, the degradation or renaturation of denatured and entangled proteins, and the quality-control of newly folded proteins all require the action of molecular chaperones. Members of all four major families of ATP-dependent molecular chaperones (chaperonin/Cpn60, Hsp70, Hsp90 and Hsp100 families) have been identified in plastids from unicellular algae to higher plants. This review aims not only at giving an overview of the most current insights into the general and conserved functions of these plastid chaperones, but also into their specific plastid functions. Given that chloroplasts harbor an extreme environment that cycles between reduced and oxidized states, that has to deal with reactive oxygen species and is highly reactive to environmental and developmental signals, it can be presumed that plastid chaperones have evolved a plethora of specific functions some of which are just about to be discovered. Here, the most urgent questions that remain unsolved are discussed, and guidance for future research on plastid chaperones is given. This article is part of a Special Issue entitled: Chloroplast Biogenesis.
Topics: Adenosine Triphosphate; HSP70 Heat-Shock Proteins; Molecular Chaperones; Oxidation-Reduction; Plastids; Protein Folding; Protein Transport
PubMed: 25596449
DOI: 10.1016/j.bbabio.2015.01.002 -
Clinical Cancer Research : An Official... Mar 2007
Review
Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Models, Biological; Molecular Chaperones; Neoplasms; Signal Transduction
PubMed: 17363512
DOI: 10.1158/1078-0432.CCR-06-2966 -
Science (New York, N.Y.) Dec 1996Molecular chaperones are essential proteins that participate in the regulation of steroid receptors in eukaryotes. The steroid aporeceptor complex contains the molecular...
Molecular chaperones are essential proteins that participate in the regulation of steroid receptors in eukaryotes. The steroid aporeceptor complex contains the molecular chaperones Hsp90 and Hsp70, p48, the cyclophilin Cyp-40, and the associated proteins p23 and p60. In vitro folding assays showed that Cyp-40 and p23 functioned as molecular chaperones in a manner similar to that of Hsp90 or Hsp70. Although neither Cyp-40 nor p23 could completely refold an unfolded substrate, both proteins interacted with the substrate to maintain a nonnative folding-competent intermediate. Thus, the steroid aporeceptor complexes have multiple chaperone components that maintain substrates in an intermediate folded state.
Topics: Amino Acid Isomerases; Carrier Proteins; Peptidyl-Prolyl Isomerase F; Cyclophilins; HSC70 Heat-Shock Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Heat-Shock Proteins; Hot Temperature; Molecular Chaperones; Peptidylprolyl Isomerase; Phosphoproteins; Prostaglandin-E Synthases; Protein Conformation; Protein Denaturation; Protein Folding; Solubility; beta-Galactosidase
PubMed: 8939864
DOI: 10.1126/science.274.5293.1718 -
International Journal of Molecular... Feb 2018The GroEL/GroES chaperonin complex acts as a folding cage by producing a bullet-like asymmetric complex, and GroEL exists as double rings regardless of the presence of...
The GroEL/GroES chaperonin complex acts as a folding cage by producing a bullet-like asymmetric complex, and GroEL exists as double rings regardless of the presence of adenosine triphosphate (ATP). Its mammalian chaperonin homolog, heat shock protein, HSP60, and co-chaperonin, HSP10, play an essential role in protein folding by capturing unfolded proteins in the HSP60/HSP10 complex. However, the structural transition in ATPase-dependent reaction cycle has remained unclear. We found nucleotide-dependent association and dissociation of the HSP60/HSP10 complex using various analytical techniques under near physiological conditions. Our results showed that HSP60 exist as a significant number of double-ring complexes (football- and bullet-type complexes) and a small number of single-ring complexes in the presence of ATP and HSP10. HSP10 binds to HSP60 in the presence of ATP, which increased the HSP60 double-ring formation. After ATP is hydrolyzed to Adenosine diphosphate (ADP), HSP60 released the HSP10 and the dissociation of the double-ring to single-rings occurred. These results indicated that HSP60/HSP10 undergoes an ATP-dependent transition between the single- and double-rings in their system that is highly distinctive from the GroEL/GroES system particularly in the manner of complex formation and the roles of ATP binding and hydrolysis in the reaction cycle.
Topics: Adenosine Triphosphate; Animals; Chaperonin 10; Chaperonin 60; Chemical Phenomena; Humans; Molecular Chaperones; Molecular Structure; Multiprotein Complexes; Protein Binding
PubMed: 29415503
DOI: 10.3390/ijms19020489 -
PloS One 2012Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer...
Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients.
Topics: Biophysics; HSP90 Heat-Shock Proteins; Hydrogen Bonding; Models, Molecular; Molecular Chaperones; Molecular Dynamics Simulation; Principal Component Analysis; Protein Conformation
PubMed: 22624053
DOI: 10.1371/journal.pone.0037605