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https://www.readbyqxmd.com/read/28389532/rna-binding-proteins-with-prion-like-domains-in-health-and-disease
#1
REVIEW
Alice Ford Harrison, James Shorter
Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease...
April 7, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28379007/avidity-for-polypeptide-binding-by-nucleotide-bound-hsp104-structures
#2
Clarissa L Weaver, Elizabeth C Duran, Korrie L Mack, JiaBei Lin, Meredith E Jackrel, Elizabeth A Sweeny, James Shorter, Aaron L Lucius
Recent Hsp104 structural studies have reported both planar and helical models of the hexameric structure. The conformation of Hsp104 monomers within the hexamer is affected by nucleotide ligation. After nucleotide-driven hexamer formation, Hsp104-catalyzed disruption of protein aggregates requires binding to the peptide substrate. Here, we examine the oligomeric state of Hsp104 and its peptide binding competency in the absence of nucleotide and in the presence of ADP, ATPγS, AMPPNP, or AMPPCP. Surprisingly, we found that only ATPγS facilitates avid peptide binding by Hsp104...
April 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/28375147/crystal-structures-of-hsp104-n-terminal-domains-from-saccharomyces-cerevisiae-and-candida-albicans-suggest-the-mechanism-for-the-function-of-hsp104-in-dissolving-prions
#3
Peng Wang, Jingzhi Li, Clarissa Weaver, Aaron Lucius, Bingdong Sha
Hsp104 is a yeast member of the Hsp100 family which functions as a molecular chaperone to disaggregate misfolded polypeptides. To understand the mechanism by which the Hsp104 N-terminal domain (NTD) interacts with its peptide substrates, crystal structures of the Hsp104 NTDs from Saccharomyces cerevisiae (ScHsp104NTD) and Candida albicans (CaHsp104NTD) have been determined at high resolution. The structures of ScHsp104NTD and CaHsp104NTD reveal that the yeast Hsp104 NTD may utilize a conserved putative peptide-binding groove to interact with misfolded polypeptides...
April 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28373280/heat-shock-protein-104-hsp104-mediated-curing-of-psi-yeast-prions-depends-on-both-psi-conformation-and-the-properties-of-the-hsp104-homologs
#4
Xiaohong Zhao, Ramon Rodriguez, Rebecca E Silberman, Joseph M Ahearn, Sheela Saidha, Kaelyn C Cummins, Daniel Masison, Evan Eisenberg, Lois E Greene
Prions arise from proteins that have two possible conformations: properly folded and non-infectious, or misfolded and infectious. The [PSI (+) ] yeast prion, which is the misfolded, self-propagating form of the translation termination factor eRF3 (Sup35), can be cured of its infectious conformation by overexpression of Hsp104, which helps dissolve the prion seeds. This dissolution depends on the trimming activity of Hsp104, which reduces the size of the prion seeds without increasing their number. To further understand the relationship between trimming and curing, trimming was followed by measuring the loss of GFP-labeled Sup35 foci from both strong and weak [PSI (+) ] variants; the former variant has more seeds and less soluble Sup35 than the latter...
April 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28298410/fus-inclusions-disrupt-rna-localization-by-sequestering-kinesin-1-and-inhibiting-microtubule-detyrosination
#5
Kyota Yasuda, Sarah F Clatterbuck-Soper, Meredith E Jackrel, James Shorter, Stavroula Mili
Cytoplasmic inclusions of the RNA-binding protein fused in sarcoma (FUS) represent one type of membraneless ribonucleoprotein compartment. Formation of FUS inclusions is promoted by amyotrophic lateral sclerosis (ALS)-linked mutations, but the cellular functions affected upon inclusion formation are poorly defined. In this study, we find that FUS inclusions lead to the mislocalization of specific RNAs from fibroblast cell protrusions and neuronal axons. This is mediated by recruitment of kinesin-1 mRNA and protein within FUS inclusions, leading to a loss of detyrosinated glutamate (Glu)-microtubules (MTs; Glu-MTs) and an inability to support the localization of RNAs at protrusions...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28293166/protein-remodeling-factors-as-potential-therapeutics-for-neurodegenerative-disease
#6
REVIEW
Meredith E Jackrel, James Shorter
Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28289075/coordinated-hsp110-and-hsp104-activities-power-protein-disaggregation-in-saccharomyces-cerevisiae
#7
Jayasankar Mohanakrishnan Kaimal, Ganapathi Kandasamy, Fabian Gasser, Claes Andréasson
Protein aggregation is intimately associated with cellular stress and is accelerated during aging, disease and cellular dysfunction. Yeast cells rely on the ATP-consuming chaperone Hsp104 to disaggregate proteins together with Hsp70. Hsp110s are ancient and abundant chaperones that form complexes with Hsp70. Here we provide in vivo data showing that yeast Hsp110s Sse1 and Sse2 are essential for Hsp104-dependent protein disaggregation. Following heat shock, complexes of Hsp110 and Hsp70 are recruited to protein aggregates and functions together with Hsp104 in the disaggregation process...
March 13, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28275610/mutant-analysis-reveals-allosteric-regulation-of-clpb-disaggregase
#8
Kamila B Franke, Bernd Bukau, Axel Mogk
The members of the hexameric AAA+ disaggregase of E. coli and S. cerevisiae, ClpB, and Hsp104, cooperate with the Hsp70 chaperone system in the solubilization of aggregated proteins. Aggregate solubilization relies on a substrate threading activity of ClpB/Hsp104 fueled by ATP hydrolysis in both ATPase rings (AAA-1, AAA-2). ClpB/Hsp104 ATPase activity is controlled by the M-domains, which associate to the AAA-1 ring to downregulate ATP hydrolysis. Keeping M-domains displaced from the AAA-1 ring by association with Hsp70 increases ATPase activity due to enhanced communication between protomers...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28241148/cytosolic-proteostasis-through-importing-of-misfolded-proteins-into-mitochondria
#9
Linhao Ruan, Chuankai Zhou, Erli Jin, Andrei Kucharavy, Ying Zhang, Zhihui Wen, Laurence Florens, Rong Li
Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins...
March 16, 2017: Nature
https://www.readbyqxmd.com/read/28208059/designer-protein-disaggregases-to-counter-neurodegenerative-disease
#10
REVIEW
James Shorter
Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90...
February 13, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28073182/over-expression-of-the-molecular-chaperone-hsp104-in-saccharomyces-cerevisiae-results-in-the-malpartition-of-psi-propagons
#11
Frederique Ness, Brian S Cox, Jintana Wongwigkarn, Wesley R Naeimi, Mick F Tuite
The ability of a yeast cell to propagate [PSI(+) ], the prion form of the Sup35 protein, is dependent on the molecular chaperone Hsp104. Inhibition of Hsp104 function in yeast cells leads to a failure to generate new propagons, the molecular entities necessary for [PSI(+) ] propagation in dividing cells and they get diluted out as cells multiply. Over-expression of Hsp104 also leads to [PSI(+) ] prion loss and this has been assumed to arise from the complete disaggregation of the Sup35 prion polymers. However, in conditions of Hsp104 over-expression in [PSI(+) ] cells we find no release of monomers from Sup35 polymers, no monomerization of aggregated Sup35 which is not accounted for by the proportion of prion-free [psi(-) ] cells present, no change in the molecular weight of Sup35-containing SDS-resistant polymers and no significant decrease in average propagon numbers in the population as a whole...
April 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28035761/analysis-of-swi-formation-and-propagation-events
#12
Zhiqiang Du, Dustin Kenneth Goncharoff, Xudong Cheng, Liming Li
The budding yeast, Saccharomyces cerevisiae, harbors several prions that are transmitted as altered, heritable protein conformations. [SWI(+) ] is one such prion whose determinant is Swi1, a subunit of the evolutionarily conserved chromatin-remodeling complex SWI/SNF. Despite the importance of Swi1, the molecular events that lead to [SWI(+) ] prionogenesis remain poorly understood. In this study, we have constructed floccullin-promoter-based URA3 reporters for [SWI(+) ] identification. Using these reporters, we show that the spontaneous formation frequency of [SWI(+) ] is significantly higher than that of [PSI(+) ] (prion form of Sup35)...
April 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/27920024/biology-and-pathobiology-of-tdp-43-and-emergent-therapeutic-strategies
#13
Lin Guo, James Shorter
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27901467/structural-basis-for-the-disaggregase-activity-and-regulation-of-hsp104
#14
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
#15
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...
December 6, 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
#16
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...
January 2017: Genetics
https://www.readbyqxmd.com/read/27815300/prions-chaperones-and-proteostasis-in-yeast
#17
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
#18
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...
November 2016: Prion
https://www.readbyqxmd.com/read/27689885/prion-aggregates-are-recruited-to-the-insoluble-protein-deposit-ipod-via-myosin-2-based-vesicular-transport
#19
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
#20
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
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