The Experts below are selected from a list of 20211 Experts worldwide ranked by ideXlab platform

Simon Alberti - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Chaperones and stress inducible protein sorting factors coordinate the spatiotemporal distribution of protein aggregates
    Molecular Biology of the Cell, 2012
    Co-Authors: Liliana Malinovska, Sonja Kroschwald, Matthias C Munder, Doris Richter, Simon Alberti
    Abstract:

    The deposition of misfolded proteins in cytoplasmic protein bodies requires the concerted action of stress-inducible protein-sorting factors and Molecular Chaperones. Protein sequestration during a...

  • Molecular Chaperones and stress inducible protein sorting factors coordinate the spatiotemporal distribution of protein aggregates
    Molecular Biology of the Cell, 2012
    Co-Authors: Liliana Malinovska, Sonja Kroschwald, Matthias C Munder, Doris Richter, Simon Alberti
    Abstract:

    Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of Molecular Chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system.

  • cooperation of Molecular Chaperones with the ubiquitin proteasome system
    Biochimica et Biophysica Acta, 2004
    Co-Authors: Claudia Esser, Simon Alberti, Jorg Hohfeld
    Abstract:

    Molecular Chaperones and energy-dependent proteases have long been viewed as opposing forces that control protein biogenesis. Molecular Chaperones are specialized in protein folding, whereas energy-dependent proteases such as the proteasome mediate efficient protein degradation. Recent data, however, suggest that Molecular Chaperones directly cooperate with the ubiquitin/proteasome system during protein quality control in eukaryotic cells. Modulating the intracellular balance of protein folding and protein degradation may open new strategies for the treatment of human diseases that involve chaperone pathways such as cancer and diverse amyloid diseases.

Richard I Morimoto - One of the best experts on this subject based on the ideXlab platform.

  • regulation of longevity in caenorhabditis elegans by heat shock factor and Molecular Chaperones
    Molecular Biology of the Cell, 2003
    Co-Authors: James F Morley, Richard I Morimoto
    Abstract:

    The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual Molecular Chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual Chaperones was to a lesser extent, suggesting an important role for networks of Chaperones. The interaction of ILS with HSF-1 could represent an important Molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.

  • chaperoning signaling pathways Molecular Chaperones as stress sensing heat shock proteins
    Journal of Cell Science, 2002
    Co-Authors: Ellen A A Nollen, Richard I Morimoto
    Abstract:

    Heat shock proteins interact with multiple key components of signaling pathways that regulate growth and development. The Molecular relationships between heat shock proteins, various signaling proteins and partner proteins appear to be critical for the normal function of signal transduction pathways. The relative levels of these proteins may be important, as too little or too much Hsp70 or Hsp90 can result in aberrant growth control, developmental malformations and cell death. Although the functions of heat shock proteins as Molecular Chaperones have been well characterized, their complementary role as a 'stress-induced' proteins to monitor changes and alter the biochemical environment of the cell remains elusive. Genetic and Molecular interactions between heat shock proteins, their co-Chaperones and components of signaling pathways suggest that crosstalk between these proteins can regulate proliferation and development by preventing or enhancing cell growth and cell death as the levels of heat shock proteins vary in response to environmental stress or disease.

  • role of the heat shock response and Molecular Chaperones in oncogenesis and cell death
    Journal of the National Cancer Institute, 2000
    Co-Authors: Caroline Jolly, Richard I Morimoto
    Abstract:

    Exposure of cells to conditions of environmental stress-including heat shock, oxidative stress, heavy metals, or pathologic conditions, such as ischemia and reperfusion, inflammation, tissue damage, infection, and mutant proteins associated with genetic diseases-results in the inducible expression of heat shock proteins that function as Molecular Chaperones or proteases. Molecular Chaperones are a class of proteins that interact with diverse protein substrates to assist in their folding, with a critical role during cell stress to prevent the appearance of folding intermediates that lead to misfolded or otherwise damaged molecules. Consequently, heat shock proteins assist in the recovery from stress either by repairing damaged proteins (protein refolding) or by degrading them, thus restoring protein homeostasis and promoting cell survival. The events of cell stress and cell death are linked, such that Molecular Chaperones induced in response to stress appear to function at key regulatory points in the control of apoptosis. On the basis of these observations-and on the role of Molecular Chaperones in the regulation of steroid aporeceptors, kinases, caspases, and other protein remodeling events involved in chromosome replication and changes in cell structure-it is not surprising that the heat shock response and Molecular Chaperones have been implicated in the control of cell growth. In this review, we address some of the Molecular and cellular events initiated by cell stress-the interrelationships between stress signaling, cell death, and oncogenesis-and Chaperones as potential targets for cancer diagnosis and treatment.

  • the heat shock response regulation and function of heat shock proteins and Molecular Chaperones
    Essays in Biochemistry, 1997
    Co-Authors: Richard I Morimoto, Michael P Kline, David N Bimston, Jose J Cotto
    Abstract:

    Abstract Exposure of cells to stresses such as heat shock, oxidant injury and heavy metals causes an imbalance in protein metabolism which challenges the cell to respond rapidly, yet precisely, to minimize the deleterious effects of environmental and physiological stress. The heat-shock response, through the activation of HSFs, results in the elevated expression of heat-shock genes and the concomitant synthesis of HSPs and Molecular Chaperones. Molecular Chaperones function in a variety of protein biosynthetic events and protect proteins from the deleterious effects of acute or chronic stress by stabilizing and refolding protein-folding intermediates or facilitating protein degradation. The accumulation of misfolded proteins has also become a central issue to diseases of protein folding, including sickle cell haemoglobin, cystic fibrosis and prion diseases, in addition to complex multifactorial diseases such as bacterial and viral infections, myocardial ischaemia, neurodegenerative diseases and cancer.

Raymond R. Townsend - One of the best experts on this subject based on the ideXlab platform.

  • In Vivo Substrates of the Lens Molecular Chaperones aA- Crystallin and aB-Crystallin
    2016
    Co-Authors: Usha P. Andley, James P. Malone, Raymond R. Townsend
    Abstract:

    aA-crystallin and aB-crystallin are members of the small heat shock protein family and function as Molecular Chaperones and major lens structural proteins. Although numerous studies have examined their chaperone-like activities in vitro, little is known about the proteins they protect in vivo. To elucidate the relationships between chaperone function, substrate binding, and human cataract formation, we used proteomic and mass spectrometric methods to analyze the effect of mutations associated with hereditary human cataract formation on protein abundance in aA-R49C and aB-R120G knock-in mutant lenses. Compared with age-matched wild type lenses, 2-day-old aA-R49C heterozygous lenses demonstrated the following: increased crosslinking (15-fold) and degradation (2.6-fold) of aA-crystallin; increased association between aA-crystallin and filensin, actin, or creatine kinase B; increased acidification of bB1-crystallin; increased levels of grifin; and an association between bA3/A1-crystallin and aA-crystallin. Homozygous aA-R49C mutant lenses exhibited increased associations between aA-crystallin and bB3-, bA4-, bA2-crystallins, and grifin, whereas levels of bB1-crystallin, gelsolin, and calpain 3 decreased. The amount of degraded glutamate dehydrogenase, a-enolase, and cytochrome c increased more than 50-fold in homozygous aA-R49C mutant lenses. In aB-R120G mouse lenses, our analyses identified decreased abundance of phosphoglycerate mutase, several b- and c-crystallins, and degradation of aA- and aB-crystallin early in cataract development. Changes in the abundance of hemoglobin and histones with the loss of normal a-crystallin chaperon

  • In vivo substrates of the lens Molecular Chaperones αA-crystallin and αB-crystallin.
    PloS one, 2014
    Co-Authors: Usha P. Andley, James P. Malone, Raymond R. Townsend
    Abstract:

    αA-crystallin and αB-crystallin are members of the small heat shock protein family and function as Molecular Chaperones and major lens structural proteins. Although numerous studies have examined their chaperone-like activities in vitro, little is known about the proteins they protect in vivo. To elucidate the relationships between chaperone function, substrate binding, and human cataract formation, we used proteomic and mass spectrometric methods to analyze the effect of mutations associated with hereditary human cataract formation on protein abundance in αA-R49C and αB-R120G knock-in mutant lenses. Compared with age-matched wild type lenses, 2-day-old αA-R49C heterozygous lenses demonstrated the following: increased crosslinking (15-fold) and degradation (2.6-fold) of αA-crystallin; increased association between αA-crystallin and filensin, actin, or creatine kinase B; increased acidification of βB1-crystallin; increased levels of grifin; and an association between βA3/A1-crystallin and αA-crystallin. Homozygous αA-R49C mutant lenses exhibited increased associations between αA-crystallin and βB3-, βA4-, βA2-crystallins, and grifin, whereas levels of βB1-crystallin, gelsolin, and calpain 3 decreased. The amount of degraded glutamate dehydrogenase, α-enolase, and cytochrome c increased more than 50-fold in homozygous αA-R49C mutant lenses. In αB-R120G mouse lenses, our analyses identified decreased abundance of phosphoglycerate mutase, several β- and γ-crystallins, and degradation of αA- and αB-crystallin early in cataract development. Changes in the abundance of hemoglobin and histones with the loss of normal α-crystallin chaperone function suggest that these proteins also play important roles in the biochemical mechanisms of hereditary cataracts. Together, these studies offer a novel insight into the putative in vivo substrates of αA- and αB-crystallin.

Johannes Buchner - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Chaperones cellular machines for protein folding
    Angewandte Chemie, 2002
    Co-Authors: Stefan Walter, Johannes Buchner
    Abstract:

    Proteins are linear polymers synthesized by ribosomes from activated amino acids. The product of this biosynthetic process is a polypeptide chain, which has to adopt the unique three-dimensional structure required for its function in the cell. In 1972, Christian Anfinsen was awarded the Nobel Prize for Chemistry for showing that this folding process is autonomous in that it does not require any additional factors or input of energy. Based on in vitro experiments with purified proteins, it was suggested that the correct three-dimensional structure can form spontaneously in vivo once the newly synthesized protein leaves the ribosome. Furthermore, proteins were assumed to maintain their native conformation until they were degraded by specific enzymes. In the last decade this view of cellular protein folding has changed considerably. It has become clear that a complicated and sophisticated machinery of proteins exists which assists protein folding and allows the functional state of proteins to be maintained under conditions in which they would normally unfold and aggregate. These proteins are collectively called Molecular Chaperones, because, like their human counterparts, they prevent unwanted interactions between their immature clients. In this review, we discuss the principal features of this peculiar class of proteins, their structure ± function relationships, and the underlying Molecular mechanisms.

  • assisting spontaneity the role of hsp90 and small hsps as Molecular Chaperones
    Trends in Biochemical Sciences, 1994
    Co-Authors: Ursula Jakob, Johannes Buchner
    Abstract:

    Hsp90 and small Hsps are two abundant types of eukaryotic stress protein whose function has remained largely enigmatic. In the cell, Hsp90 exists in a complex (with other Hsps and prolyl isomerases) possibly implicated in interactions with non-native proteins. Recent biochemical analysis of both Hsp90 and small Hsps has revealed that they may act as ATP-independent Molecular Chaperones involved in protein folding and unfolding events.

  • small heat shock proteins are Molecular Chaperones
    Journal of Biological Chemistry, 1993
    Co-Authors: Ursula Jakob, Matthias Gaestel, Katrin Engel, Johannes Buchner
    Abstract:

    Abstract Small heat shock proteins (sHsp) with a Molecular mass of 15-30 kDa are ubiquitous and conserved. Up to now their function has remained enigmatic. Increased expression under heat shock conditions and their protective effect on cell viability at elevated temperatures suggest that they may have a function in the formation or maintenance of the native conformation of cytosolic proteins. To test this hypothesis we studied the influence of murine Hsp25, human Hsp27, and bovine alpha-B-crystallin (an eye lens protein homologous to sHsps) on the unfolding and refolding of citrate synthase and alpha-glucosidase in vitro. Here we show that all sHsps investigated act as Molecular Chaperones in these folding reactions. At stoichiometric amounts they maximally prevent the aggregation of citrate synthase and alpha-glucosidase under heat shock conditions and stabilize the proteins. Furthermore, they promote the functional refolding of these proteins after urea denaturation similar to GroE and Hsp90. The interaction both with unfolding and refolding proteins seems to be ATP-independent.

Jacob Verghese - One of the best experts on this subject based on the ideXlab platform.

  • The nucleotide exchange factors of Hsp70 Molecular Chaperones.
    Frontiers in molecular biosciences, 2015
    Co-Authors: Andreas Bracher, Jacob Verghese
    Abstract:

    Molecular Chaperones of the Hsp70 family form an important hub in the cellular protein folding networks in bacteria and eukaryotes, connecting translation with the downstream machineries of protein folding and degradation. The Hsp70 folding cycle is driven by two types of coChaperones: J-domain proteins stimulate ATP hydrolysis by Hsp70, while nucleotide exchange factors (NEFs) promote replacement of Hsp70-bound ADP with ATP. Bacteria and organelles of bacterial origin have only one known NEF type for Hsp70, GrpE. In contrast, a large diversity of Hsp70 NEFs has been discovered in the eukaryotic cell. These NEFs belong to the Hsp110/Grp170, HspBP1/Sil1, and BAG domain protein families. In this short review we compare the structures and Molecular mechanisms of nucleotide exchange factors for Hsp70 and discuss how these coChaperones contribute to protein folding and quality control in the cell.

  • grpe hsp110 grp170 hspbp1 sil1 and bag domain proteins nucleotide exchange factors for hsp70 Molecular Chaperones
    Sub-cellular biochemistry, 2015
    Co-Authors: Andreas Bracher, Jacob Verghese
    Abstract:

    Molecular Chaperones of the Hsp70 family are key components of the cellular protein folding machinery. Substrate folding is accomplished by iterative cycles of ATP binding, hydrolysis and release. The ATPase activity of Hsp70 is regulated by two main classes of coChaperones: J-domain proteins stimulate ATPase hydrolysis by Hsp70, while nucleotide exchange factors (NEF) facilitate its conversion from the ADP-bound to the ATP-bound state, thus closing the chaperone folding cycle. Beginning with the discovery of the prototypical bacterial NEF GrpE, a large diversity of Hsp70 nucleotide exchange factors has been identified, connecting Hsp70 to a multitude of cellular processes in the eukaryotic cell. Here we review recent advances towards structure and function of nucleotide exchange factors from the Hsp110/Grp170, HspBP1/Sil1 and BAG domain protein families and discuss how these coChaperones connect protein folding with quality control and degradation pathways.