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https://www.readbyqxmd.com/read/29353403/genetic-polymorphism-in-hsp90aa1-gene-is-associated-with-the-thermotolerance-in-chinese-holstein-cows
#1
T M Badri, K L Chen, M A Alsiddig, Lian Li, Yafei Cai, G L Wang
The heat shock protein 90 (Hsp90) is a copious and ubiquitous molecular chaperone which plays an essential role in many cellular biological processes. The objective of this study was to identify single nucleotide polymorphisms (SNPs) in the Hsp90AA1 gene and to determine their association with heat stress traits in Chinese Holstein cattle breed. Direct sequencing was used to identify new SNPs. Luciferase reporter assay methods were used to assess g.- 87G > C and g.4172A > G loci in the promoter activity and 3'-UTR, respectively...
January 20, 2018: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/29352646/synthesis-and-biological-evaluation-of-anti-cancer-agents-that-selectively-inhibit-her2-over-expressed-breast-cancer-cell-growth-via-down-regulation-of-her2-protein
#2
Anran Zhao, Qiaoyun Zheng, Cody M Orahoske, Nethrie D Idippily, Morgan M Ashcraft, Aicha Quamine, Bin Su
Compound JCC76 selectively inhibited the proliferation of human epidermal growth factor 2 (Her2) over-expressed breast cancer cells. In the current study, a ligand based structural optimization was performed to generate new analogs, and we identified derivatives 16 and 17 that showed improved activity and selectivity against Her2 positive breast cancer cells. A structure activity relationship (SAR) was summarized. Compounds 16 and 17 were also examined by western blot assay to check their effect on Her2 protein...
January 12, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29351844/interactome-screening-identifies-the-er-luminal-chaperone-hsp47-as-a-regulator-of-the-unfolded-protein-response-transducer-ire1%C3%AE
#3
Denisse Sepulveda, Diego Rojas-Rivera, Diego A Rodríguez, Jody Groenendyk, Andres Köhler, Cynthia Lebeaupin, Shinya Ito, Hery Urra, Amado Carreras-Sureda, Younis Hazari, Mireille Vasseur-Cognet, Maruf M U Ali, Eric Chevet, Gisela Campos, Patricio Godoy, Tomas Vaisar, Béatrice Bailly-Maitre, Kazuhiro Nagata, Marek Michalak, Jimena Sierralta, Claudio Hetz
Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29351843/cellular-handling-of-protein-aggregates-by-disaggregation-machines
#4
REVIEW
Axel Mogk, Bernd Bukau, Harm H Kampinga
Both acute proteotoxic stresses that unfold proteins and expression of disease-causing mutant proteins that expose aggregation-prone regions can promote protein aggregation. Protein aggregates can interfere with cellular processes and deplete factors crucial for protein homeostasis. To cope with these challenges, cells are equipped with diverse folding and degradation activities to rescue or eliminate aggregated proteins. Here, we review the different chaperone disaggregation machines and their mechanisms of action...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29351842/maintaining-a-healthy-proteome-during-oxidative-stress
#5
REVIEW
Dana Reichmann, Wilhelm Voth, Ursula Jakob
Some of the most challenging stress conditions that organisms encounter during their lifetime involve the transient accumulation of reactive oxygen and chlorine species. Extremely reactive to amino acid side chains, these oxidants cause widespread protein unfolding and aggregation. It is therefore not surprising that cells draw on a variety of different strategies to counteract the damage and maintain a healthy proteome. Orchestrated largely by direct changes in the thiol oxidation status of key proteins, the response strategies involve all layers of protein protection...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29351602/the-integrity-and-organization-of-the-human-aipl1-functional-domains-is-critical-for-its-role-as-a-hsp90-dependent-co-chaperone-for-rod-pde6
#6
Almudena Sacristan-Reviriego, James Bellingham, Chrisostomos Prodromou, Annika N Boehm, Annette Aichem, Neruban Kumaran, James Bainbridge, Michel Michaelides, Jacqueline van der Spuy
No abstract text is available yet for this article.
January 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29348817/a-mitochondrial-targeted-purine-based-hsp90-antagonist-for-leukemia-therapy
#7
Kelly G Bryant, Young Chan Chae, Rogelio L Martinez, John C Gordon, Khaled M Elokely, Andrew V Kossenkov, Steven Grant, Wayne E Childers, Magid Abou-Gharbia, Dario C Altieri
Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π contacts and hydrophobic interactions with the surrounding amino acids in the active site...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348634/a-biosensor-based-framework-to-measure-latent-proteostasis-capacity
#8
Rebecca J Wood, Angelique R Ormsby, Mona Radwan, Dezerae Cox, Abhishek Sharma, Tobias Vöpel, Simon Ebbinghaus, Mikael Oliveberg, Gavin E Reid, Alex Dickson, Danny M Hatters
The pool of quality control proteins (QC) that maintains protein-folding homeostasis (proteostasis) is dynamic but can become depleted in human disease. A challenge has been in quantitatively defining the depth of the QC pool. With a new biosensor, flow cytometry-based methods and mathematical modeling we measure the QC capacity to act as holdases and suppress biosensor aggregation. The biosensor system comprises a series of barnase kernels with differing folding stability that engage primarily with HSP70 and HSP90 family proteins...
January 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29348557/sensitizing-tumor-cells-to-conventional-drugs-hsp70-chaperone-inhibitors-their-selection-and-application-in-cancer-models
#9
Vladimir F Lazarev, Dmitry V Sverchinsky, Elena R Mikhaylova, Pavel I Semenyuk, Elena Y Komarova, Sergey A Niskanen, Alina D Nikotina, Anton V Burakov, Viktor G Kartsev, Irina V Guzhova, Boris A Margulis
Hsp70 chaperone controls proteostasis and anti-stress responses in rapidly renewing cancer cells, making it an important target for therapeutic compounds. To date several Hsp70 inhibitors are presented with remarkable anticancer activity, however their clinical application is limited by the high toxicity towards normal cells. This study aimed to develop assays to search for the substances that reduce the chaperone activity of Hsp70 and diminish its protective function in cancer cells. On our mind the resulting compounds alone should be safe and function in combination with drugs widely employed in oncology...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29346421/the-absence-of-specific-yeast-heat-shock-proteins-leads-to-abnormal-aggregation-and-compromised-autophagic-clearance-of-mutant-huntingtin-proteins
#10
Ryan Higgins, Marie-Helene Kabbaj, Alexa Hatcher, Yanchang Wang
The functionality of a protein depends on its correct folding, but newly synthesized proteins are susceptible to aberrant folding and aggregation. Heat shock proteins (HSPs) function as molecular chaperones that aid in protein folding and the degradation of misfolded proteins. Trinucleotide (CAG) repeat expansion in the Huntingtin gene (HTT) results in the expression of misfolded Huntingtin protein (Htt), which contributes to the development of Huntington's disease. We previously found that the degradation of mutated Htt with polyQ expansion (Htt103QP) depends on both ubiquitin proteasome system and autophagy...
2018: PloS One
https://www.readbyqxmd.com/read/29346364/mutations-in-caenorhabditis-elegans-neuroligin-like-glit-1-the-apoptosis-pathway-and-the-calcium-chaperone-crt-1-increase-dopaminergic-neurodegeneration-after-6-ohda-treatment
#11
Sarah-Lena Offenburger, Elisabeth Jongsma, Anton Gartner
The loss of dopaminergic neurons is a hallmark of Parkinson's disease, the aetiology of which is associated with increased levels of oxidative stress. We used C. elegans to screen for genes that protect dopaminergic neurons against oxidative stress and isolated glit-1 (gliotactin (Drosophila neuroligin-like) homologue). Loss of the C. elegans neuroligin-like glit-1 causes increased dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative-stress inducing drug that is specifically taken up into dopaminergic neurons...
January 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29345620/functional-role-of-the-type-1-pilus-rod-structure-in-mediating-host-pathogen-interactions
#12
Caitlin N Spaulding, Henry Louis Schreiber, Weili Zheng, Karen W Dodson, Jennie E Hazen, Matt S Conover, Fengbin Wang, Pontus Svenmarker, Areli Luna-Rico, Olivera Francetic, Magnus Andersson, Scott Hultgren, Edward H Egelman
Uropathogenic E. coli (UPEC), which cause urinary tract infections (UTI), utilize type 1 pili, a chaperone usher pathway (CUP) pilus, to cause UTI and colonize the gut. The pilus rod, comprised of repeating FimA subunits, provides a structural scaffold for displaying the tip adhesin, FimH. We solved the 4.2 Å resolution structure of the type 1 pilus rod using cryo-electron microscopy. Residues forming the interactive surfaces that determine the mechanical properties of the rod were maintained by selection based on a global alignment of fimA sequences...
January 18, 2018: ELife
https://www.readbyqxmd.com/read/29343782/protein-phosphatase-5-regulates-titin-phosphorylation-and-function-at-a-sarcomere-associated-mechanosensor-complex-in-cardiomyocytes
#13
Judith Krysiak, Andreas Unger, Lisa Beckendorf, Nazha Hamdani, Marion von Frieling-Salewsky, Margaret M Redfield, Cris G Dos Remedios, Farah Sheikh, Ulrich Gergs, Peter Boknik, Wolfgang A Linke
Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29343704/phosphorylation-induced-cochaperone-unfolding-promotes-kinase-recruitment-and-client-class-specific-hsp90-phosphorylation
#14
Ashleigh B Bachman, Dimitra Keramisanou, Wanping Xu, Kristin Beebe, Michael A Moses, M V Vasantha Kumar, Geoffrey Gray, Radwan Ebna Noor, Arjan van der Vaart, Len Neckers, Ioannis Gelis
During the Hsp90-mediated chaperoning of protein kinases, the core components of the machinery, Hsp90 and the cochaperone Cdc37, recycle between different phosphorylation states that regulate progression of the chaperone cycle. We show that Cdc37 phosphorylation at Y298 results in partial unfolding of the C-terminal domain and the population of folding intermediates. Unfolding facilitates Hsp90 phosphorylation at Y197 by unmasking a phosphopeptide sequence, which serves as a docking site to recruit non-receptor tyrosine kinases to the chaperone complex via their SH2 domains...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29343244/hsp70-at-the-membrane-driving-protein-translocation
#15
REVIEW
Elizabeth A Craig
Efficient movement of proteins across membranes is required for cell health. The translocation process is particularly challenging when the channel in the membrane through which proteins must pass is narrow-such as those in the membranes of the endoplasmic reticulum and mitochondria. Hsp70 molecular chaperones play roles on both sides of these membranes, ensuring efficient translocation of proteins synthesized on cytosolic ribosomes into the interior of these organelles. The "import motor" in the mitochondrial matrix, which is essential for driving the movement of proteins across the mitochondrial inner membrane, is arguably the most complex Hsp70-based system in the cell...
January 17, 2018: BMC Biology
https://www.readbyqxmd.com/read/29342862/heterogeneous-contributing-factors-in-mpm-disease-development-and-progression-biological-advances-and-clinical-implications
#16
REVIEW
Bhairavi Tolani, Luis A Acevedo, Ngoc T Hoang, Biao He
Malignant pleural mesothelioma (MPM) tumors are remarkably aggressive and most patients only survive for 5-12 months; irrespective of stage; after primary symptoms appear. Compounding matters is that MPM remains unresponsive to conventional standards of care; including radiation and chemotherapy. Currently; instead of relying on molecular signatures and histological typing; MPM treatment options are guided by clinical stage and patient characteristics because the mechanism of carcinogenesis has not been fully elucidated; although about 80% of cases can be linked to asbestos exposure...
January 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29341298/multiple-signaling-systems-target-a-core-set-of-transition-metal-homeostasis-genes-using-similar-binding-motifs
#17
M E Garber, L Rajeev, A E Kazakov, J Trinh, D Masuno, M G Thompson, N Kaplan, J Luk, P S Novichkov, A Mukhopadhyay
Bacterial response to metals can require complex regulation. We report an overlapping regulation for copper and zinc resistance genes in the denitrifying bacterium, Pseudomonas stutzeri RCH2, by three two-component regulatory proteins CopR1, CopR2 and CzcR. We conducted genome-wide evaluations to identify gene targets of two paralogous regulators, CopR1 and CopR2, annotated for copper signaling, and compared the results with the gene targets for CzcR, implicated in zinc signaling. We discovered that the CopRs and CzcR have largely common targets, and cross-regulate a core set of P...
January 17, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29340620/delivery-of-tapasin-modified-ctl-epitope-peptide-via-cytoplasmic-transduction-peptide-induces-ctls-by-jak-stat-signaling-pathway-in-vivo
#18
Shanshan Wu, Xiaohua Chen, Yuyan Tang, Yi Zhang, Dan Li, Jie Chen, Jieling Wang, Zhenghao Tang, Guoqing Zang, Yongsheng Yu
Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) play a vital role in viral control and clearance. Recent studies have elucidated that Tapasin, an endoplasmic reticulum chaperone, is a well-known molecule that appears to be essential in peptide-loading process. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays an important role in immune response regulation and cytokines secretion. We have previously verified that fusion protein CTP-HBcAg18-27-Tapasin could facilitate the maturation of bone marrow derived dendritic cells and enhance specific CTLs responses in vitro, which might be associated with the activation of JAK/STAT signaling pathway...
January 11, 2018: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29339748/dot1-regulates-nucleosome-dynamics-by-its-inherent-histone-chaperone-activity-in-yeast
#19
Soyun Lee, Seunghee Oh, Kwiwan Jeong, Hyelim Jo, Yoonjung Choi, Hogyu David Seo, Minhoo Kim, Joonho Choe, Chang Seob Kwon, Daeyoup Lee
Dot1 (disruptor of telomeric silencing-1, DOT1L in humans) is the only known enzyme responsible for histone H3 lysine 79 methylation (H3K79me) and is evolutionarily conserved in most eukaryotes. Yeast Dot1p lacks a SET domain and does not methylate free histones and thus may have different actions with respect to other histone methyltransferases. Here we show that Dot1p displays histone chaperone activity and regulates nucleosome dynamics via histone exchange in yeast. We show that a methylation-independent function of Dot1p is required for the cryptic transcription within transcribed regions seen following disruption of the Set2-Rpd3S pathway...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29339544/role-of-chromatin-damage-and-chromatin-trapping-of-fact-in-mediating-the-anticancer-cytotoxicity-of-dna-binding-small-molecule-drugs
#20
Elimelech Nesher, Alfiya Safina, Ieman Aljahdali, Scott Portwood, Eunice S Wang, Igor Koman, Jianmin Wang, Katerina V Gurova
Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from chromatin damage in cells. Recent work on curaxins, a class of small molecule drugs with broad anticancer activity, show that they interfere with histone-DNA interactions and destabilize nucleosomes without binding DNA or causing detectable DNA damage. Chromatin unfolding caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes and causes chromatin trapping (c-trapping)...
January 16, 2018: Cancer Research
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