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https://www.readbyqxmd.com/read/27901467/structural-basis-for-the-disaggregase-activity-and-regulation-of-hsp104
#1
Alexander Heuck, Sonja Schitter-Sollner, Marcin Józef Suskiewicz, Robert Kurzbauer, Juliane Kley, Alexander Schleiffer, Pascaline Rombaut, Franz Herzog, Tim Clausen
The Hsp104 disaggregase is a two-ring ATPase machine that rescues various forms of non-native proteins including the highly resistant amyloid fibers. The structural-mechanistic underpinnings of how the recovery of toxic protein aggregates is promoted and how this potent unfolding activity is prevented from doing collateral damage to cellular proteins are not well understood. Here, we present structural and biochemical data revealing the organization of Hsp104 from Chaetomium thermophilum at 3.7 Å resolution...
November 30, 2016: ELife
https://www.readbyqxmd.com/read/27872278/reconstitution-of-a-mycobacterium-tuberculosis-proteostasis-network-highlights-essential-cofactor-interactions-with-chaperone-dnak
#2
Tania J Lupoli, Allison Fay, Carolina Adura, Michael S Glickman, Carl F Nathan
During host infection, Mycobacterium tuberculosis (Mtb) encounters several types of stress that impair protein integrity, including reactive oxygen and nitrogen species and chemotherapy. The resulting protein aggregates can be resolved or degraded by molecular machinery conserved from bacteria to eukaryotes. Eukaryotic Hsp104/Hsp70 and their bacterial homologs ClpB/DnaK are ATP-powered chaperones that restore toxic protein aggregates to a native folded state. DnaK is essential in Mycobacterium smegmatis, and ClpB is involved in asymmetrically distributing damaged proteins during cell division as a mechanism of survival in Mtb, commending both proteins as potential drug targets...
November 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27866167/rewiring-of-signaling-networks-modulating-thermotolerance-in-the-human-pathogen-cryptococcus-neoformans
#3
Dong-Hoon Yang, Kwang-Woo Jung, Soohyun Bang, Jang-Won Lee, Min-Hee Song, Anna Floyd-Averette, Richard A Festa, Giuseppe Ianiri, Alexander Idnurm, Dennis J Thiele, Joseph Heitman, Yong-Sun Bahn
Thermotolerance is a crucial virulence attribute for human pathogens, including the fungus Cryptococcus neoformans that causes fatal meningitis in humans. Loss of the protein kinase Sch9 increases C. neoformans thermotolerance, but its regulatory mechanism has remained unknown. Here, we studied the Sch9-dependent and Sch9-independent signaling networks modulating C. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. During temperature upshift, genes encoding for molecular chaperones and heat shock proteins were upregulated, whereas those for translation, transcription, and sterol biosynthesis were highly suppressed...
November 18, 2016: Genetics
https://www.readbyqxmd.com/read/27815300/prions-chaperones-and-proteostasis-in-yeast
#4
Tatiana A Chernova, Keith D Wilkinson, Yury O Chernoff
Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based heritable elements that serve as an excellent experimental system for studying prion biology. The propagation of yeast prions is controlled by the same Hsp104/70/40 chaperone machinery that is involved in the protection of yeast cells against proteotoxic stress. Ribosome-associated chaperones, proteolytic pathways, cellular quality-control compartments, and cytoskeletal networks influence prion formation, maintenance, and toxicity...
November 4, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27690738/the-small-heat-shock-protein-hsp31-cooperates-with-hsp104-to-modulate-sup35-prion-aggregation
#5
Kiran Aslam, Chai-Jui Tsai, Tony R Hazbun
The yeast homolog of DJ-1, Hsp31, is a multifunctional protein that is involved in several cellular pathways including detoxification of the toxic metabolite methylglyoxal and as a protein deglycase. Prior studies ascribed Hsp31 as a molecular chaperone that can inhibit α-Syn aggregation in vitro and alleviate its toxicity in vivo. It was also shown that Hsp31 inhibits Sup35 aggregate formation in yeast, however, it is unknown if Hsp31 can modulate [PSI(+)] phenotype and Sup35 prionogenesis. Other small heat shock proteins, Hsp26 and Hsp42 are known to be a part of a synergistic proteostasis network that inhibits Sup35 prion formation and promotes its disaggregation...
October 3, 2016: Prion
https://www.readbyqxmd.com/read/27689885/prion-aggregates-are-recruited-to-the-insoluble-protein-deposit-ipod-via-myosin-2-based-vesicular-transport
#6
Rajesh Kumar, Peter P Nawroth, Jens Tyedmers
Aggregation of amyloidogenic proteins is associated with several neurodegenerative diseases. Sequestration of misfolded and aggregated proteins into specialized deposition sites may reduce their potentially detrimental properties. Yeast exhibits a distinct deposition site for amyloid aggregates termed "Insoluble PrOtein Deposit (IPOD)", but nothing is known about the mechanism of substrate recruitment to this site. The IPOD is located directly adjacent to the Phagophore Assembly Site (PAS) where the cell initiates autophagy and the Cytoplasm-to-Vacuole Targeting (CVT) pathway destined for delivery of precursor peptidases to the vacuole...
September 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27633137/protein-folding-activity-of-the-ribosome-is-involved-in-yeast-prion-propagation
#7
Marc Blondel, Flavie Soubigou, Justine Evrard, Phu Hai Nguyen, Naushaba Hasin, Stéphane Chédin, Reynald Gillet, Marie-Astrid Contesse, Gaëlle Friocourt, Guillaume Stahl, Gary W Jones, Cécile Voisset
6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI(+)] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI(+)]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI(+)] propagation...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27616763/bacterial-and-yeast-aaa-disaggregases-clpb-and-hsp104-operate-through-conserved-mechanism-involving-cooperation-with-hsp70
#8
Eva Kummer, Anna Szlachcic, Kamila B Franke, Sophia Ungelenk, Bernd Bukau, Axel Mogk
Escherichia coli ClpB and Saccharomyces cerevisiae Hsp104 are members of the Hsp100 family of ring-forming hexameric AAA+ chaperones that promote the solubilization of aggregated proteins and the propagation of prions. ClpB and Hsp104 cooperate with cognate Hsp70 chaperones for substrate targeting and activation of ATPase and substrate threading, achieved by transient Hsp70 binding to the repressing ClpB/Hsp104 M-domain. Fundamental differences in ATPase regulation and disaggregation mechanisms have been reported; however, these differences are raising doubts regarding the working principle of this AAA+ chaperone...
October 23, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27544759/fluorescence-microscopic-analysis-of-antifungal-effects-of-cold-atmospheric-pressure-plasma-in-saccharomyces-cerevisiae
#9
Koki Itooka, Kazuo Takahashi, Shingo Izawa
Cold atmospheric pressure plasma (CAP) has potential to be utilized as an alternative method for sterilization in food industries without thermal damage or toxic residues. In contrast to the bactericidal effects of CAP, information regarding the efficacy of CAP against eukaryotic microorganisms is very limited. Therefore, herein we investigated the effects of CAP on the budding yeast Saccharomyces cerevisiae, with a focus on the cellular response to CAP. The CAP treatment caused oxidative stress responses including the nuclear accumulation of the oxidative stress responsive transcription factor Yap1, mitochondrial fragmentation, and enhanced intracellular oxidation...
November 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27498190/phosphatidylinositol-3-phosphate-regulates-response-of-cells-to-proteotoxic-stress
#10
Joanna Kaminska, Weronika Rzepnikowska, Anna Polak, Krzysztof Flis, Piotr Soczewka, Katarzyna Bala, Marzena Sienko, Marcin Grynberg, Pawel Kaliszewski, Agnieszka Urbanek, Kathryn Ayscough, Teresa Zoladek
Human Nedd4 ubiquitin ligase, or its variants, inhibit yeast cell growth by disturbing the actin cytoskeleton organization and dynamics, and lead to an increase in levels of ubiquitinated proteins. In a screen for multicopy suppressors which rescue growth of yeast cells producing Nedd4 ligase with an inactive WW4 domain (Nedd4w4), we identified a fragment of ATG2 gene encoding part of the Atg2 core autophagy protein. Expression of the Atg2-C1 fragment (aa 1074-1447) improved growth, actin cytoskeleton organization, but did not significantly change the levels of ubiquitinated proteins in these cells...
October 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27497973/mutation-of-a-regulator-ask10p-improves-xylose-isomerase-activity-through-up-regulation-of-molecular-chaperones-in-saccharomyces-cerevisiae
#11
Jin Hou, Chunlei Jiao, Bo Peng, Yu Shen, Xiaoming Bao
Economically feasible bioconversion of lignocelluloses into fuels and chemicals is dependent on efficient utilization of all available sugars in lignocellulosic biomass, including hextose and pentose. Previously, we constructed a xylose fermenting strain of Saccharomyces cerevisiae through metabolic engineering and enhanced its xylose utilization capability through evolutionary engineering. However, the key mechanism of improved xylose utilization and xylose isomerase activity was not identified. In this study, we applied the concept of inverse metabolic engineering to identify the factors involved in improving xylose utilization...
August 4, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27478928/spiral-architecture-of-the-hsp104-disaggregase-reveals-the-basis-for-polypeptide-translocation
#12
Adam L Yokom, Stephanie N Gates, Meredith E Jackrel, Korrie L Mack, Min Su, James Shorter, Daniel R Southworth
Hsp104, a conserved AAA+ protein disaggregase, promotes survival during cellular stress. Hsp104 remodels amyloids, thereby supporting prion propagation, and disassembles toxic oligomers associated with neurodegenerative diseases. However, a definitive structural mechanism for its disaggregase activity has remained elusive. We determined the cryo-EM structure of wild-type Saccharomyces cerevisiae Hsp104 in the ATP state, revealing a near-helical hexamer architecture that coordinates the mechanical power of the 12 AAA+ domains for disaggregation...
September 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27373154/asymmetric-inheritance-of-aggregated-proteins-and-age-reset-in-yeast-are-regulated-by-vac17-dependent-vacuolar-functions
#13
Sandra Malmgren Hill, Xinxin Hao, Johan Grönvall, Stephanie Spikings-Nordby, Per O Widlund, Triana Amen, Anna Jörhov, Rebecca Josefson, Daniel Kaganovich, Beidong Liu, Thomas Nyström
Age can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae, we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan...
July 19, 2016: Cell Reports
https://www.readbyqxmd.com/read/27264606/lifespan-control-by-redox-dependent-recruitment-of-chaperones-to-misfolded-proteins
#14
Sarah Hanzén, Katarina Vielfort, Junsheng Yang, Friederike Roger, Veronica Andersson, Sara Zamarbide-Forés, Rebecca Andersson, Lisa Malm, Gael Palais, Benoît Biteau, Beidong Liu, Michel B Toledano, Mikael Molin, Thomas Nyström
Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress...
June 30, 2016: Cell
https://www.readbyqxmd.com/read/27255695/engineering-therapeutic-protein-disaggregases
#15
James Shorter
Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding...
May 15, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27223323/adenosine-diphosphate-restricts-the-protein-remodeling-activity-of-the-hsp104-chaperone-to-hsp70-assisted-disaggregation
#16
Agnieszka Kłosowska, Tomasz Chamera, Krzysztof Liberek
Hsp104 disaggregase provides thermotolerance in yeast by recovering proteins from aggregates in cooperation with the Hsp70 chaperone. Protein disaggregation involves polypeptide extraction from aggregates and its translocation through the central channel of the Hsp104 hexamer. This process relies on adenosine triphosphate (ATP) hydrolysis. Considering that Hsp104 is characterized by low affinity towards ATP and is strongly inhibited by adenosine diphosphate (ADP), we asked how Hsp104 functions at the physiological levels of adenine nucleotides...
2016: ELife
https://www.readbyqxmd.com/read/27179072/aggregation-dynamics-and-identification-of-aggregation-prone-mutants-of-the-von-hippel-lindau-tumor-suppressor-protein
#17
Xavier Le Goff, Franck Chesnel, Olivier Delalande, Anne Couturier, Stéphane Dréano, Cathy Le Goff, Cécile Vigneau, Yannick Arlot-Bonnemains
Quality control mechanisms promote aggregation and degradation of misfolded proteins. In budding yeast, the human von Hippel-Lindau protein (pVHL, officially known as VHL) is misfolded and forms aggregates. Here, we investigated the aggregation of three pVHL isoforms (pVHL213, pVHL160, pVHL172) in fission yeast. The full-length pVHL213 isoform aggregates in highly dynamic small puncta and in large spherical inclusions, either close to the nucleus or to the cell ends. The large inclusions contain the yeast Hsp104 chaperone...
July 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27074685/kinetics-of-formation-and-asymmetrical-distribution-of-hsp104-bound-protein-aggregates-in-yeast
#18
Camille Paoletti, Sophie Quintin, Audrey Matifas, Gilles Charvin
Budding yeast cells have a finite replicative life span; that is, a mother cell produces only a limited number of daughter cells before it slows division and dies. Despite the gradual aging of the mother cell, all daughters are born rejuvenated and enjoy a full replicative lifespan. It has been proposed that entry of mother cells into senescence is driven by the progressive accumulation and retention of damaged material, including protein aggregates. This additionally allows the daughter cells to be born damage free...
April 12, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27050154/experimental-milestones-in-the-discovery-of-molecular-chaperones-as-polypeptide-unfolding-enzymes
#19
Andrija Finka, Rayees U H Mattoo, Pierre Goloubinoff
Molecular chaperones control the cellular folding, assembly, unfolding, disassembly, translocation, activation, inactivation, disaggregation, and degradation of proteins. In 1989, groundbreaking experiments demonstrated that a purified chaperone can bind and prevent the aggregation of artificially unfolded polypeptides and use ATP to dissociate and convert them into native proteins. A decade later, other chaperones were shown to use ATP hydrolysis to unfold and solubilize stable protein aggregates, leading to their native refolding...
June 2, 2016: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/27014702/engineering-and-evolution-of-molecular-chaperones-and-protein-disaggregases-with-enhanced-activity
#20
REVIEW
Korrie L Mack, James Shorter
Cells have evolved a sophisticated proteostasis network to ensure that proteins acquire and retain their native structure and function. Critical components of this network include molecular chaperones and protein disaggregases, which function to prevent and reverse deleterious protein misfolding. Nevertheless, proteostasis networks have limits, which when exceeded can have fatal consequences as in various neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis. A promising strategy is to engineer proteostasis networks to counter challenges presented by specific diseases or specific proteins...
2016: Frontiers in Molecular Biosciences
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