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Progress in Retinal and Eye Research Jul 2008Molecular chaperones facilitate and regulate protein conformational change within cells. This encompasses many fundamental cellular processes: including the correct... (Review)
Review
Molecular chaperones facilitate and regulate protein conformational change within cells. This encompasses many fundamental cellular processes: including the correct folding of nascent chains; protein transport and translocation; signal transduction and protein quality control. Chaperones are, therefore, important in several forms of human disease, including neurodegeneration. Within the retina, the highly specialized photoreceptor cell presents a fascinating paradigm to investigate the specialization of molecular chaperone function and reveals unique chaperone requirements essential to photoreceptor function. Mutations in several photoreceptor proteins lead to protein misfolding mediated neurodegeneration. The best characterized of these are mutations in the molecular light sensor, rhodopsin, which cause autosomal dominant retinitis pigmentosa. Rhodopsin biogenesis is likely to require chaperones, while rhodopsin misfolding involves molecular chaperones in quality control and the cellular response to protein aggregation. Furthermore, the specialization of components of the chaperone machinery to photoreceptor specific roles has been revealed by the identification of mutations in molecular chaperones that cause inherited retinal dysfunction and degeneration. These chaperones are involved in several important cellular pathways and further illuminate the essential and diverse roles of molecular chaperones.
Topics: Animals; Humans; Molecular Chaperones; Photoreceptor Cells, Vertebrate; Retinal Degeneration
PubMed: 18490186
DOI: 10.1016/j.preteyeres.2008.03.001 -
Cell Cycle (Georgetown, Tex.) Sep 2004Heat shock proteins (hsps) are versatile molecular chaperones that are responsible for many cellular functions including proper folding, oligomeric assembly, activation,... (Review)
Review
Heat shock proteins (hsps) are versatile molecular chaperones that are responsible for many cellular functions including proper folding, oligomeric assembly, activation, and transport of proteins. Most of the known roles for hsps involve intracellular proteins and processes. Mounting evidence suggests that hsps are present and function in the extracellular space. Hsp90alpha was recently found on the surface and in conditioned media of HT-1080 fibrosarcoma cells. Here it acts as a molecular chaperone that assists in the activation of matrix metalloproteinase-2 (MMP2), leading to increased tumor invasiveness. Few other extracellular substrates of hsp90 have been identified, but several independent observations of extracellular hsp90 suggest that this protein may be important for both normal physiology and disease states. Hsp90 typically works in a complex of associated proteins, and some of these proteins have also been observed extracellularly. Here we show that some of these components, including hsp90 organizing protein (hop) and p23, are also found in HT-1080 conditioned media supporting the notion that hsp90 complexes function in invasiveness. These findings suggest a wide-ranging phenomenon of extracellular molecular chaperoning that could have implications for biological processes and disease.
Topics: Animals; Extracellular Matrix; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Intramolecular Oxidoreductases; Macromolecular Substances; Matrix Metalloproteinase 2; Molecular Chaperones; Neoplasm Invasiveness; Phosphoproteins; Prostaglandin-E Synthases
PubMed: 15326368
DOI: No ID Found -
International Journal of Molecular... Feb 2022Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain... (Review)
Review
Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain proteins, which involves multiple steps of segmental folding, is one of the biggest questions in protein science. Multidomain protein folding often requires the assistance of molecular chaperones. Molecular chaperones promote or delay the folding of the client protein, but the detailed mechanisms are still unclear. This review summarizes the findings of biophysical and structural studies on the mechanism of multidomain protein folding mediated by molecular chaperones and explains how molecular chaperones recognize the client proteins and alter their folding properties. Furthermore, we introduce several recent studies that describe the concept of kinetics-activity relationships to explain the mechanism of functional diversity of molecular chaperones.
Topics: Humans; Kinetics; Molecular Chaperones; Protein Folding
PubMed: 35269628
DOI: 10.3390/ijms23052485 -
Essays in Biochemistry Sep 2023Yeast is a valuable model organism for their ease of genetic manipulation, rapid growth rate, and relative similarity to higher eukaryotes. Historically, Saccharomyces...
Yeast is a valuable model organism for their ease of genetic manipulation, rapid growth rate, and relative similarity to higher eukaryotes. Historically, Saccharomyces cerevisiae has played a major role in discovering the function of complex proteins and pathways that are important for human health and disease. Heat shock protein 90 (Hsp90) is a molecular chaperone responsible for the stabilization and activation of hundreds of integral members of the cellular signaling network. Much important structural and functional work, including many seminal discoveries in Hsp90 biology are the direct result of work carried out in S. cerevisiae. Here, we have provided a brief overview of the S. cerevisiae model system and described how this eukaryotic model organism has been successfully applied to the study of Hsp90 chaperone function.
Topics: Humans; Saccharomyces cerevisiae; Molecular Chaperones; HSP90 Heat-Shock Proteins; Saccharomyces cerevisiae Proteins
PubMed: 36912239
DOI: 10.1042/EBC20220224 -
Journal of Visualized Experiments : JoVE Mar 2022Biomolecular interactions play versatile roles in numerous cellular processes by regulating and coordinating functionally relevant biological events. Biomolecules such...
Biomolecular interactions play versatile roles in numerous cellular processes by regulating and coordinating functionally relevant biological events. Biomolecules such as proteins, carbohydrates, vitamins, fatty acids, nucleic acids, and enzymes are fundamental building blocks of living beings; they assemble into complex networks in biosystems to synchronize a myriad of life events. Proteins typically utilize complex interactome networks to carry out their functions; hence it is mandatory to evaluate such interactions to unravel their importance in cells at both cellular and organism levels. Toward this goal, we introduce a rapidly emerging technology, field-effect biosensing (FEB), to determine specific biomolecular interactions. FEB is a benchtop, label-free, and reliable biomolecular detection technique to determine specific interactions and uses high-quality electronic-based biosensors. The FEB technology can monitor interactions in the nanomolar range due to the biocompatible nanomaterials used on its biosensor surface. As a proof of concept, the protein-protein interaction (PPI) between heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) was elucidated. Hsp90 is an ATP-dependent molecular chaperone that plays an essential role in the folding, stability, maturation, and quality control of many proteins, thereby regulating multiple vital cellular functions. Cdc37 is regarded as a protein kinase-specific molecular chaperone, as it specifically recognizes and recruits protein kinases to Hsp90 to regulate their downstream signal transduction pathways. As such, Cdc37 is considered a co-chaperone of Hsp90. The chaperone-kinase pathway (Hsp90/Cdc37 complex) is hyper-activated in multiple malignancies promoting cellular growth; therefore, it is a potential target for cancer therapy. The present study demonstrates the efficiency of FEB technology using the Hsp90/Cdc37 model system. FEB detected a strong PPI between the two proteins (KD values of 0.014 µM, 0.053 µM, and 0.072 µM in three independent experiments). In summary, FEB is a label-free and cost-effective PPI detection platform, which offers fast and accurate measurements.
Topics: Cell Cycle Proteins; Chaperonins; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Binding; Protein Kinases; Technology
PubMed: 35435890
DOI: 10.3791/63495 -
Biochemical and Biophysical Research... Jan 2014Although several phloem sap proteins have been identified from protein extracts of heat-treated Arabidopsis seedlings using FPLC gel filtration columns, many of the...
Although several phloem sap proteins have been identified from protein extracts of heat-treated Arabidopsis seedlings using FPLC gel filtration columns, many of the physiological roles played by these proteins remain to be elucidated. We functionally characterized a phloem protein 2-A1, which encodes a protein similar to phloem lectin. Using a bacterially expressed recombinant protein of AtPP2-A1, we found that it performs dual functions, showing both molecular chaperone activity and antifungal activity. mRNA expression of the AtPP2-1 gene was induced by diverse external stresses such as pathogens, and other signaling molecules, such as ethylene. These results suggest that the AtPP2-A1 molecular chaperone protein plays a critical role in the Arabidopsis defense system against diverse external stresses including fungal pathogenic attack and heat shock.
Topics: Arabidopsis; Arabidopsis Proteins; Fungi; Molecular Chaperones; Plant Lectins; Stress, Physiological
PubMed: 24269669
DOI: 10.1016/j.bbrc.2013.11.034 -
Cells Aug 2022Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various... (Review)
Review
Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various diseases. The essential molecular chaperone Hsp90 is a regulator of the heat shock response via HSF1 and a stabilizer of a plethora of signaling proteins. In this review, we summarize the role of Hsp90 in the cellular and organismal regulation of proteome maintenance.
Topics: HSP90 Heat-Shock Proteins; Heat-Shock Response; Molecular Chaperones; Proteome; Proteostasis
PubMed: 36010556
DOI: 10.3390/cells11162479 -
International Journal of Molecular... Apr 2022Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3,... (Review)
Review
Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin-proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.
Topics: Amyotrophic Lateral Sclerosis; Heat-Shock Proteins; Humans; Molecular Chaperones; Mutation; Protein Folding; Superoxide Dismutase-1
PubMed: 35456894
DOI: 10.3390/ijms23084076 -
Oncogene Oct 2008Molecular chaperones have been reported as multifunctional antistress molecules that can regulate diverse biological processes to maintain cellular homeostasis.... (Review)
Review
Molecular chaperones have been reported as multifunctional antistress molecules that can regulate diverse biological processes to maintain cellular homeostasis. Molecular chaperones have critical roles for maintaining proper protein folding, protein translocation, degradation of unfolded protein, regulating signal-transduction proteins and so on. Under pathological conditions, inducible or constitutively expressed molecular chaperones protect cells from stress. Non-dividing terminally differentiated cells accumulate abnormal proteins due to chronic environmental or physiological stress; thus, proper chaperone function is critical for maintaining homeostasis of those cells, such as neuronal and muscular cells. Cancer cells also have overexpression of molecular chaperone proteins for promoting survival from stress related to growth, cell cycle, hypoxia, metastasis and genetic mutations. Here, we will focus on the function of molecular chaperone proteins for the regulation of cell death in degenerative diseases, ischemic diseases and in cancer.
Topics: Animals; Cell Death; Humans; Ischemia; Mice; Molecular Chaperones; Neoplasms; Neurodegenerative Diseases
PubMed: 18955975
DOI: 10.1038/onc.2008.314 -
Sub-cellular Biochemistry 2015Hsp90 is a conserved molecular chaperone and is responsible for the folding and activation of several hundred client proteins, involved in various cellular processes.... (Review)
Review
Hsp90 is a conserved molecular chaperone and is responsible for the folding and activation of several hundred client proteins, involved in various cellular processes. The large number and the diversity of these client proteins demand a high adaptiveness of Hsp90 towards the need of the individual client. This adaptiveness is amongst others mediated by more than 20 so-called cochaperones that differ in their actions towards Hsp90. Some of these cochaperones are able to modulate the ATPase activity of Hsp90 and/or its client protein binding, folding and activation. p23 and Aha1 are two prominent examples with opposing effects on the ATPase activity of Hsp90. p23 is able to inhibit the ATP turnover while Aha1 is the strongest known activator of the ATPase activity of Hsp90. Even though both cochaperones are conserved from yeast to man and have been studied for years, some Hsp90-related as well as Hsp90-independent functions are still enigmatic and under current investigation. In this chapter, we first introduce the ATPase cycle of Hsp90 and then focus on the two cochaperones integrating them in the Hsp90 cycle.
Topics: Animals; HSP90 Heat-Shock Proteins; Humans; Intramolecular Oxidoreductases; Models, Molecular; Molecular Chaperones; Prostaglandin-E Synthases; Protein Conformation; Protein Folding; Signal Transduction; Structure-Activity Relationship
PubMed: 25487019
DOI: 10.1007/978-3-319-11731-7_6