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Unfolded Proteins

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https://www.readbyqxmd.com/read/28821864/nanomechanics-of-multidomain-neuronal-cell-adhesion-protein-contactin-revealed-by-single-molecule-afm-and-smd
#1
K Mikulska-Ruminska, A J Kulik, C Benadiba, I Bahar, G Dietler, W Nowak
Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. CNTN4 consists of six immunoglobulin C2 type (IgC2) domains and four fibronectin type III (FnIII) domains that are shared with many other CAMs. Mutations in CNTN4 gene have been linked to various psychiatric disorders. Toward elucidating the response of this modular protein to mechanical stress, we studied its force-induced unfolding using single molecule atomic force microscopy (smAFM) and steered molecular dynamics (SMD) simulations...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28820582/pathogenic-mutations-induce-partial-structural-changes-in-native-%C3%AE-sheet-structure-of-transthyretin-and-accelerate-aggregation
#2
Kwang Hun Lim, Anvesh K R Dasari, Renze Ma, Ivan Hung, Zhehong Gan, Jeffery W Kelly, Michael C Fitzgerald
Amyloid formation of natively folded proteins involves global and/or local unfolding of the native state to form aggregation-prone intermediates. Here we report solid-state NMR structural studies of amyloid derived from wild-type (WT) and more aggressive mutant forms of transthyretin (TTR) to investigate the structural changes associated with effective TTR aggregation. We employed selective 13C-labeling schemes to investigate structural features of β-structured core regions in amyloid states of WT and two mutant forms (V30M and L55P) of TTR...
August 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28817203/the-combination-of-digoxin-and-gsk2606414-exerts-synergistic-anticancer-activity-against-leukemia-in-vitro-and-in-vivo
#3
Xue-Hong Zhang, Xin-Yu Wang, Zhi-Wei Zhou, Hua Bai, Lin Shi, Yin-Xue Yang, Shu-Feng Zhou, Xiao-Chun Zhang
Digoxin is a member of cardiac glycosides and recent studies show that digoxin plays anticancer role in several types of cancer. However, the anticancer effects and mechanism of digoxin in leukemia is largely unknown. Her, our data show that digoxin treatment significantly inhibits leukemia cell viability. In addition, digoxin treatment significantly induced apoptosis and G2/M cell cycle arrest in leukemia cells. Furthermore, we demonstrated that digoxin treatment inactivate that oncogenic pathway Akt/mTOR signaling in leukemia cells...
August 17, 2017: BioFactors
https://www.readbyqxmd.com/read/28816360/c-c-motif-chemokine-ligand-2-regulates-lps-induced-inflammation-and-er-stress-to-enhance-proliferation-of-bovine-endometrial-epithelial-cells
#4
Whasun Lim, Hyocheol Bae, Fuller W Bazer, Sung-Man Kim, Gwonhwa Song
Chemokines play an important role in regulating the complex immune system at the maternal-fetal interface during pregnancy. Among various chemokines, C-C motif chemokine ligand 2 (CCL2) plays a role in the recruitment of immune regulatory cells to implantation sites within the endometrium. In cattle, CCL2 is abundantly expressed in the uterine endometrium. However, its intracellular signaling has not been identified. In this study, we examined the effects of CCL2 on bovine endometrial (BEND) cell proliferation...
August 17, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28815872/a-multimethod-computational-simulation-approach-for-investigating-mitochondrial-dynamics-and-dysfunction-in-degenerative-aging
#5
Timothy E Hoffman, Katherine J Barnett, Lyle Wallis, William H Hanneman
Research in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans...
August 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/28815041/-upregulation-of-cd47-by-the-endoplasmic-reticulum-stress-pathway-controls-anti-tumor-immune-responses
#6
Katherine L Cook, David R Soto-Pantoja
We recently demonstrated that targeting the unfolded protein response (UPR) protein GRP78 down-regulates CD47 expression, resulting in increased tumor macrophage infiltration and inhibited resistance to anti-estrogen therapy. We now show new data indicating that anti-estrogen therapy regulates CD47 expression and implicates its ligand, thrombospondin-1, in regulation of tumor macrophage infiltration. Moreover, GRP78 and CD47 co-expression is associated with poor prognosis in breast cancer patients, suggesting the existence of crosstalk between UPR and immunity that regulates therapeutic responses in breast cancer...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28815021/toward-an-understanding-of-the-cdc48-p97-atpase
#7
REVIEW
Nicholas Bodnar, Tom Rapoport
A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore...
2017: F1000Research
https://www.readbyqxmd.com/read/28814986/2-deoxy-d-glucose-restore-glucocorticoid-sensitivity-in-acute-lymphoblastic-leukemia-via-modification-of-n-linked-glycosylation-in-an-oxygen-tension-independent-manner
#8
Zaira Leni, Paulina Ćwiek, Valeriya Dimitrova, Andrea S Dulcey, Nicola Zamboni, Cedric Simillion, Geetha Rossi, Kurt Leibundgut, Alexandre Arcaro
In childhood acute lymphoblastic leukemia, treatment failure is associated with resistance to glucocorticoid agents. Resistance to this class of drugs represents one of the strongest indicators of poor clinical outcome. We show that leukemic cells, which are resistant to the glucocorticoid drug methylprednisolone, display a higher demand of glucose associated with a deregulation of metabolic pathways, in comparison to sensitive cells. Interestingly, a combinatorial treatment of glucocorticoid and the glucose analog 2-deoxy-D-glucose displayed a synergistic effect in methylprednisolone-resistant cells, in an oxygen tension-independent manner...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28814717/drosophila-protease-clpxp-specifically-degrades-dmlrpprc1-controlling-mitochondrial-mrna-and-translation
#9
Yuichi Matsushima, Yuta Hirofuji, Masamune Aihara, Song Yue, Takeshi Uchiumi, Laurie S Kaguni, Dongchon Kang
ClpXP is the major protease in the mitochondrial matrix in eukaryotes, and is well conserved among species. ClpXP is composed of a proteolytic subunit, ClpP, and a chaperone-like subunit, ClpX. Although it has been proposed that ClpXP is required for the mitochondrial unfolded protein response, additional roles for ClpXP in mitochondrial biogenesis are unclear. Here, we found that Drosophila leucine-rich pentatricopeptide repeat domain-containing protein 1 (DmLRPPRC1) is a specific substrate of ClpXP. Depletion or introduction of catalytically inactive mutation of ClpP increases DmLRPPRC1 and causes non-uniform increases of mitochondrial mRNAs, accumulation of some unprocessed mitochondrial transcripts, and modest repression of mitochondrial translation in Drosophila Schneider S2 cells...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813482/cysteine-rich-protein-2-accelerates-actin-filament-cluster-formation
#10
Takanori Kihara, Yasunobu Sugimoto, Satoko Shinohara, Shunpei Takaoka, Jun Miyake
Filamentous actin (F-actin) forms many types of structures and dynamically regulates cell morphology and movement, and plays a mechanosensory role for extracellular stimuli. In this study, we determined that the smooth muscle-related transcription factor, cysteine-rich protein 2 (CRP2), regulates the supramolecular networks of F-actin. The structures of CRP2 and F-actin in solution were analyzed by small-angle X-ray solution scattering (SAXS). The general shape of CRP2 was partially unfolded and relatively ellipsoidal in structure, and the apparent cross sectional radius of gyration (Rc) was about 15...
2017: PloS One
https://www.readbyqxmd.com/read/28813137/site-a-mediated-partial-unfolding-of-cytochrome-c-on-cardiolipin-vesicles-is-species-dependent-and-does-not-require-lys72
#11
Margaret M Elmer-Dixon, Bruce E Bowler
Measurements at pH 8 allow evaluation of binding of 100% cardiolipin vesicles to site A of cytochrome c without interference from other known binding sites. Site A encompasses Lys72, Lys73, Lys86 and Lys87, located in or adjacent to Ω-loop D (residues 70-85), which positions Met80 for binding to the heme. Binding of cytochrome c to cardiolipin disrupts Met80 heme binding, permitting peroxidase activity. Cardiolipin binding to yeast iso-1-cytochrome c versus human cytochrome c is compared to assess how cardiolipin binding to site A has evolved for cytochrome c from species that do not have a complete intrinsic apoptotic pathway to species that do...
August 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28812069/the-sensitivity-of-folding-free-energy-landscapes-of-trpzips-to-mutations-in-the-hydrophobic-core
#12
Madhulika Gupta, Prabir Khatua, Charusita Chakravarty, Sanjoy Bandyopadhyay
The sensitivity of the stability of folded states and free energy landscapes to the differences in the hydrophobic content of the core residues has been studied for the set of 16-residue trpzips, namely, Trpzip4, Trpzip5 and Trpzip6. The combination of principal component analysis and different secondary structure order metrics as reaction coordinates has been used to characterize and identify all the underlying attractive basins corresponding to the folded and the unfolded states for each trpzip at 300 K. Our results reveal that even a single mutation in the hydrophobic core perturbs the stability of the folded peptide and the conformational preferences for the partially folded and unfolded states significantly, leading to concomitant alterations in the free energy landscape of trpzips...
August 16, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28811582/a-new-class-of-hybrid-secretion-system-is-employed-in-pseudomonas-amyloid-biogenesis
#13
Sarah L Rouse, William J Hawthorne, Jamie-Lee Berry, Dror S Chorev, Sandra A Ionescu, Sebastian Lambert, Fisentzos Stylianou, Wiebke Ewert, Uma Mackie, R Marc L Morgan, Daniel Otzen, Florian-Alexander Herbst, Per H Nielsen, Morten Dueholm, Hagan Bayley, Carol V Robinson, Stephen Hare, Stephen Matthews
Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction of a biofilm matrix. The secretion of bacterial functional amyloid requires a bespoke outer-membrane protein channel through which unfolded amyloid substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into the functional amyloid transporter from Pseudomonas, FapF...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28811527/atherosusceptible-shear-stress-activates-endoplasmic-reticulum-stress-to-promote-endothelial-inflammation
#14
Keith A Bailey, Fawaz G Haj, Scott I Simon, Anthony G Passerini
Atherosclerosis impacts arteries where disturbed blood flow renders the endothelium susceptible to inflammation. Cytokine activation of endothelial cells (EC) upregulates VCAM-1 receptors that target monocyte recruitment to atherosusceptible regions. Endoplasmic reticulum (ER) stress elicits EC dysregulation in metabolic syndrome. We hypothesized that ER plays a central role in mechanosensing of atherosusceptible shear stress (SS) by signaling enhanced inflammation. Aortic EC were stimulated with low-dose TNFα (0...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811318/the-%C3%AE-cell-assassin-iapp-cytotoxicity
#15
Daniel Raleigh, Xiaoxue Zhang, Benoit Hastoy, Anne Clark
Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in Type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation...
August 15, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28808322/neuroinflammation-alters-cellular-proteostasis-by-producing-endoplasmic-reticulum-stress-autophagy-activation-and-disrupting-erad-activation
#16
Cristina Pintado, Sandra Macías, Helena Domínguez-Martín, Angélica Castaño, Diego Ruano
Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD)...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808004/critical-structural-fluctuations-of-proteins-upon-thermal-unfolding-challenge-the-lindemann-criterion
#17
Marina Katava, Guillaume Stirnemann, Marco Zanatta, Simone Capaccioli, Maria Pachetti, K L Ngai, Fabio Sterpone, Alessandro Paciaroni
Internal subnanosecond timescale motions are key for the function of proteins, and are coupled to the surrounding solvent environment. These fast fluctuations guide protein conformational changes, yet their role for protein stability, and for unfolding, remains elusive. Here, in analogy with the Lindemann criterion for the melting of solids, we demonstrate a common scaling of structural fluctuations of lysozyme protein embedded in different environments as the thermal unfolding transition is approached. By combining elastic incoherent neutron scattering and advanced molecular simulations, we show that, although different solvents modify the protein melting temperature, a unique dynamical regime is attained in proximity of thermal unfolding in all solvents that we tested...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807826/structural-plasticity-of-t4-transcription-co-activator-gp33-revealed-by-a-protease-resistant-unfolded-state
#18
Radhakrishnan Mahalakshmi, Svetlana Rajkumar Maurya, Bhawna Burdak, Parini Surti, Manoj S Patel, Vikas Jain
Gene 33 protein (gp33) is a transcriptional coactivator for late genes of the T4 bacteriophage. gp33 possesses a 5-helix bundle core, with unstructured N- and C-terminal regions that account for >50% of the protein sequence. It plays a unique role of interacting with host RNA polymerase, couples transcription with DNA replication, and plays the dual function as repressor and co-activator in phage transcription. Here, we identify protein structural plasticity as the molecular basis of the dual nature in gp33...
August 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28806087/size-dependent-relationships-between-protein-stability-and-thermal-unfolding-temperature-have-important-implications-for-analysis-of-protein-energetics-and-high-throughput-assays-of-protein-ligand-interactions
#19
Matthew Douglas Watson, Jeremy Monroe, Daniel P Raleigh
Changes in protein stability are commonly reported as changes in the melting temperature, ΔTM, or as changes in unfolding free energy at a particular temperature, ΔΔG°. Using data for 1124 mutants from 16 proteins we examine the relationship between ΔΔG° and ΔTM. A linear relationship is observed for each protein. The slopes of the plots of ΔTM vs ΔΔG° for different proteins scale as N(-1) where N is the number of residues in the protein. Thus, a given change in ΔG° causes a much larger change in TM for a small protein relative to the effect observed for a large protein...
August 14, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28805214/the-low-populated-folding-intermediate-of-a-mutant-of-the-fyn-sh3-domain-identified-by-a-simple-model
#20
Jing Wu, Guojun Chen, Zhuqing Zhang, Ping Zhang, Tao Chen
Experimental studies indicate that the A39V/N53P/V55L Fyn SH3 domain folds from the unfolded state to the native state via a low-populated on-pathway intermediate, whereas the folding of the wildtype is two-state-like. To get insights into the biophysical basis of their different folding mechanisms, we used native-centric models with and without additional transferrable, sequence-dependent nonnative hydrophobic interactions to study the folding behaviors of the Fyn SH3 domain and its mutant. The pure native-centric model predicts that both the wildtype and the mutant fold in a two-state manner, without any detectable intermediate...
August 14, 2017: Physical Chemistry Chemical Physics: PCCP
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