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https://www.readbyqxmd.com/read/28436957/pyruvate-kinase-m2-activation-may-protect-against-the-progression-of-diabetic-glomerular-pathology-and-mitochondrial-dysfunction
#1
Weier Qi, Hillary A Keenan, Qian Li, Atsushi Ishikado, Aimo Kannt, Thorsten Sadowski, Mark A Yorek, I-Hsien Wu, Samuel Lockhart, Lawrence J Coppey, Anja Pfenninger, Chong Wee Liew, Guifen Qiang, Alison M Burkart, Stephanie Hastings, David Pober, Christopher Cahill, Monika A Niewczas, William J Israelsen, Liane Tinsley, Isaac E Stillman, Peter S Amenta, Edward P Feener, Matthew G Vander Heiden, Robert C Stanton, George L King
Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated...
April 24, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28435250/sl2b-aptamer-and-folic-acid-dual-targeting-dna-nanostructures-for-synergic-biological-effect-with-chemotherapy-to-combat-colorectal-cancer
#2
Pengchao Sun, Nan Zhang, Yafang Tang, Yanan Yang, Xiao Chu, Yongxing Zhao
DNA nanostructures prepared by self-assembly possess good stability, high biocompatibility, and low immunogenicity as drug delivery vehicles. In this work, DNA tetrahedron (TD) was constructed and modified with SL2B aptamer (S) and folic acid (F). TD possessed a small diameter (~6 nm) and entered into the nucleus quickly. SL2B aptamer can inhibit cancer cell growth by disturbing vascular endothelial growth factor/Notch signaling pathways. To explore the effect of SL2B number on colorectal cancer inhibition, SL2B multimers (dimer, trimer, and tetramer) were constructed by functionalization of TD with different numbers of SL2B...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28432302/a-bacterial-abc-transporter-enables-import-of-mammalian-host-glycosaminoglycans
#3
Sayoko Oiki, Bunzo Mikami, Yukie Maruyama, Kousaku Murata, Wataru Hashimoto
Glycosaminoglycans (GAGs), such as hyaluronan, chondroitin sulfate, and heparin, constitute mammalian extracellular matrices. The uronate and amino sugar residues in hyaluronan and chondroitin sulfate are linked by 1,3-glycoside bond, while heparin contains 1,4-glycoside bond. Some bacteria target GAGs as means of establishing colonization and/or infection, and bacterial degradation mechanisms of GAGs have been well characterized. However, little is known about the bacterial import of GAGs. Here, we show a GAG import system, comprised of a solute-binding protein (Smon0123)-dependent ATP-binding cassette (ABC) transporter, in the pathogenic Streptobacillus moniliformis...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429932/thermodynamics-of-the-thermal-denaturation-of-acid-molten-globule-state-of-cytochrome-c-indicate-a-reversible-high-temperature-oligomerization-process
#4
Shigeyoshi Nakamura, Tomonori Saotome, Akiko Nakazawa, Masao Fukuda, Yutaka Kuroda, Shun-Ichi Kidokoro
In this study, we performed differential scanning calorimetry (DSC) and pressure perturbation calorimetry (PPC) analysis of the thermal transition of cytochrome c from an acidic molten globule (MG) state with the protein concentrations of 0.5-18.2 mg/mL. DSC profiles were highly reversible and showed clear protein-concentration dependence, indicating that reversible oligomerization occurred accompanying the thermal transition from the MG state. The DSC and PPC data required at least a six-state model including three new oligomeric states: dimer (I2), trimer (I3), and tetramer (I4) in addition to the three monomeric states previously characterized...
April 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28426764/structural-characterization-of-core-bradavidin-in-complex-with-biotin
#5
Nitin Agrawal, Juha A E Määttä, Markku S Kulomaa, Vesa P Hytönen, Mark S Johnson, Tomi T Airenne
Bradavidin is a tetrameric biotin-binding protein similar to chicken avidin and bacterial streptavidin, and was originally cloned from the nitrogen-fixing bacteria Bradyrhizobium diazoefficiens. We have previously reported the crystal structure of the full-length, wild-type (wt) bradavidin with 138 amino acids, where the C-terminal residues Gly129-Lys138 ("Brad-tag") act as an intrinsic ligand (i.e. Gly129-Lys138 bind into the biotin-binding site of an adjacent subunit within the same tetramer) and has potential as an affinity tag for biotechnological purposes...
2017: PloS One
https://www.readbyqxmd.com/read/28424304/giant-axonal-neuropathy-alters-the-structure-of-keratin-intermediate-filaments-in-human-hair
#6
Asfia Soomro, Richard J Alsop, Atsuko Negishi, Laurent Kreplak, Douglas Fudge, Edward R Kuczmarski, Robert D Goldman, Maikel C Rheinstädter
Giant axonal neuropathy (GAN) follows an autosomal recessive genetic inheritance and impedes the peripheral and central nervous system due to axonal swellings that are packed with neurofilaments. The patients display a number of phenotypes, including hypotonia, muscle weakness, decreased reflexes, ataxia, seizures, intellectual disability, pale skin and often curled hair. We used X-ray diffraction and tensile testing to determine potential changes to the structure of keratin intermediate filaments (IFs) in the hair of patients with GAN...
April 2017: Journal of the Royal Society, Interface
https://www.readbyqxmd.com/read/28416203/the-s4-s5-linker-gearbox-of-trp-channel-gating
#7
REVIEW
Laura Hofmann, Hongmei Wang, Wang Zheng, Stephan E Philipp, Patricia Hidalgo, Adolfo Cavalié, Xing-Zhen Chen, Andreas Beck, Veit Flockerzi
Transient receptor potential (TRP) channels are cation channels which participate in a wide variety of physiological processes in organisms ranging from fungi to humans. They fulfill roles in body homeostasis, are sensors for noxious chemicals and temperature in the mammalian somatosensory system and are activated by light stimulated phospholipase C activity in Drosophila or by hypertonicity in yeast. The transmembrane topology of TRP channels is similar to that of voltage-gated cation channels. TRP proteins assemble as tetramers with each subunit containing six transmembrane helices (S1-S6) and intracellular N- and C-termini...
April 4, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28414156/modeling-of-interactions-between-functional-domains-of-aldh1l1
#8
David A Horita, Sergey A Krupenko
ALDH1L1, a member of the aldehyde dehydrogenase superfamily of enzymes, catalyzes the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2. The enzyme is a tetramer of identical subunits, with each subunit consisting of three functional domains that originated from unrelated genes. The N- and C-terminal domains are catalytic, while the intermediate domain transfers the reaction intermediate from the N- to the C-terminal domain. The intermediate domain is an acyl carrier protein, possessing the covalently attached 4'-phosphopantetheine (4-PP) prosthetic group...
April 14, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28411463/simultaneous-separation-of-taxon-specific-crystallins-from-mule-duck-and-characterization-of-their-enzymatic-activities-and-structures
#9
Chih-Hsien Wang, Chia-Chi Huang, Wenlung Chen
Methods to obtain pure proteins in large amounts are indispensible in protein research. We report here a large-scale/simultaneous isolation of taxon-specific crystallins (ɛ- and δ-crystallin) from the eye lenses of Mule duck. We also investigate the compositions, enzymatic activities, and structures of these purified taxon-specific proteins. A relatively mild method of ion-exchange chromatography was developed to fractionate ɛ-crystallin and δ-crystallin in large amount, ca. ∼6.60mg/g-lens and ∼41.0mg/g-lens, respectively...
April 6, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28406893/the-chemical-basis-for-electrical-signaling
#10
REVIEW
William A Catterall, Goragot Wisedchaisri, Ning Zheng
Electrical signals generated by minute currents of ions moving across cell membranes are central to all rapid processes in biology. Initiation and propagation of electrical signals requires voltage-gated sodium (NaV) and calcium (CaV) channels. These channels contain a tetramer of membrane-bound subunits or domains comprising a voltage sensor and a pore module. Voltage-dependent activation occurs as membrane depolarization drives outward movements of positive gating changes in the voltage sensor via a sliding-helix mechanism, which leads to a conformational change in the pore module that opens its intracellular activation gate...
April 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28401214/chemo-enzymatic-synthesis-of-equisetin
#11
Xiaojun Li, Qingfei Zheng, Jun Yin, Wen Liu, Shuanhu Gao
We here report that the biosynthesis of equisetin, a fungal tetramate natural product with potent anti-infectious activity, relies on Fsa2, a Diels-Alderase that constructs the trans-decalin system of the molecule in a stereo-selective manner. This finding led to the development of a concise chemo-enzymatic route toward the synthesis of equisetin, which involves facile preparation of a linear polyene precursor via 7-steps and Fsa2 activity for equisetin maturation through an intramolecular Diels-Alder reaction, thus exemplifying the significance of the combination of chemical and biological methods to achieve structurally complex cyclic natural products and their derivatives...
April 12, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28398045/conformational-effects-through-hydrogen-bonding-in-a-constrained-%C3%AE-peptide-template-from-intraresidue-seven-membered-rings-to-a-gel-forming-sheet-structure
#12
Hawraà Awada, Claire M Grison, Florence Charnay-Pouget, Jean-Pierre Baltaze, François Brisset, Régis Guillot, Sylvie Robin, Ali Hachem, Nada Jaber, Daoud Naoufal, Ogaritte Yazbeck, David J Aitken
A series of three short oligomers (di-, tri-, and tetramers) of cis-2-(aminomethyl)cyclobutane carboxylic acid, a γ-amino acid featuring a cyclobutane ring constraint, were prepared, and their conformational behavior was examined spectroscopically and by molecular modeling. In dilute solutions, these peptides showed a number of low-energy conformers, including ribbonlike structures pleated around a rarely observed series of intramolecular seven-membered hydrogen bonds. In more concentrated solutions, these interactions defer to an organized supramolecular assembly, leading to thermoreversible organogel formation notably for the tripeptide, which produced fibrillar xerogels...
April 21, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28396859/electron-microscopy-structural-insights-into-cpap-oligomeric-behavior-a-plausible-assembly-process-of-a-supramolecular-scaffold-of-the-centrosome
#13
Ana L Alvarez-Cabrera, Sandra Delgado, David Gil-Carton, Gulnahar B Mortuza, Guillermo Montoya, Carlos O S Sorzano, Tang K Tang, Jose M Carazo
Centrosomal P4.1-associated protein (CPAP) is a cell cycle regulated protein fundamental for centrosome assembly and centriole elongation. In humans, the region between residues 897-1338 of CPAP mediates interactions with other proteins and includes a homodimerization domain. CPAP mutations cause primary autosomal recessive microcephaly and Seckel syndrome. Despite of the biological/clinical relevance of CPAP, its mechanistic behavior remains unclear and its C-terminus (the G-box/TCP domain) is the only part whose structure has been solved...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28393633/csp-1103-chf5074-stabilizes-human-transthyretin-in-healthy-human-subjects
#14
Lixia Qiang, Yanxia Guan, Xiangshun Li, Li Liu, Yanshuang Mu, Aki Sugano, Yutaka Takaoka, Toshiyuki Sakaeda, Bruno P Imbimbo, Ken-Ichi Yamamura, Shoude Jin, Zhenghua Li
Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity. In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site...
April 10, 2017: Amyloid: the International Journal of Experimental and Clinical Investigation
https://www.readbyqxmd.com/read/28389591/cd11c-expressing-cells-affect-regulatory-t-cell-behavior-in-the-meninges-during-central-nervous-system-infection
#15
Carleigh A O'Brien, Christopher Overall, Christoph Konradt, Aisling C O'Hara Hall, Nikolas W Hayes, Sagie Wagage, Beena John, David A Christian, Christopher A Hunter, Tajie H Harris
Regulatory T cells (Tregs) play an important role in the CNS during multiple infections, as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, Tregs in the CNS during T. gondii infection are Th1 polarized, as exemplified by their T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4(+) T cells, an MHC class II tetramer reagent specific for T...
April 7, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28389153/synthesis-of-pyrrole-imidazole-polyamide-oligomers-based-on-a-copper-catalyzed-cross-coupling-strategy
#16
Naoki Shiga, Shihori Takayanagi, Risa Muramoto, Tasuku Murakami, Rui Qin, Yuta Suzuki, Ken-Ichi Shinohara, Atsushi Kaneda, Tetsuhiro Nemoto
Pyrrole-imidazole (Py-Im) polyamides are useful tools for chemical biology and medicinal chemistry studies due to their unique binding properties to the minor groove of DNA. We developed a novel method of synthesizing Py-Im polyamide oligomers based on a Cu-catalyzed cross-coupling strategy. All four patterns of dimer fragments could be synthesized using a Cu-catalyzed Ullmann-type cross-coupling with easily prepared monomer units. Moreover, we demonstrated that pyrrole dimer, trimer, and tetramer building blocks for Py-Im polyamide synthesis were accessible by combining site selective iodination of the pyrrole/pyrrole coupling adduct...
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28388966/vaccination-with-poly-ic-lc-and-peptide-pulsed-autologous-dendritic-cells-in-patients-with-pancreatic-cancer
#17
Shikhar Mehrotra, Carolyn D Britten, Steve Chin, Elizabeth Garrett-Mayer, Colleen A Cloud, Mingli Li, Gina Scurti, Mohamed L Salem, Michelle H Nelson, Melanie B Thomas, Chrystal M Paulos, Andres M Salazar, Michael I Nishimura, Mark P Rubinstein, Zihai Li, David J Cole
BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from the peripheral blood of HLA-A2(+) patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV...
April 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28381790/the-wd40-domain-of-hira-is-essential-for-ri-nucleosome-assembly-in-xenopus-egg-extracts
#18
Ruibin Zhu, Mari Iwabuchi, Keita Ohsumi
Histone chaperones are a group of histone-binding proteins that facilitate the assembly of nucleosomes, the fundamental structural units of chromatin in eukaryotes. In nucleosome assembly, deposition of a histone H3-H4 tetramer onto DNA is the first and critical step, which is mediated by the histone chaperones HIRA and CAF-1. HIRA and CAF-1 are reportedly involved in DNA replication independent (RI) and replication coupled nucleosome assembly, respectively. However, the mechanisms by which they mediate histone deposition remain unclear...
2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28379186/establishment-of-the-inducible-tet-on-system-for-the-activation-of-the-silent-trichosetin-gene-cluster-in-fusarium-fujikuroi
#19
Slavica Janevska, Birgit Arndt, Leonie Baumann, Lisa Helene Apken, Lucas Maciel Mauriz Marques, Hans-Ulrich Humpf, Bettina Tudzynski
The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly related to the notorious rice pathogen Fusarium fujikuroi. Here we present the activation and characterization of a homologous, but silent, gene cluster in F. fujikuroi. Bioinformatic analysis revealed that this cluster does not contain the equisetin N-methyltransferase gene eqxD and consequently, trichosetin was isolated as final product...
April 5, 2017: Toxins
https://www.readbyqxmd.com/read/28376341/myotonic-dystrophy-approach-to-therapy
#20
REVIEW
Charles A Thornton, Eric Wang, Ellie M Carrell
Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG triplet repeat in DMPK, whereas DM type 2 is caused by expansion of a CCTG tetramer repeat in CNBP. In both cases the DM mutations lead to expression of dominant-acting RNAs. Studies of RNA toxicity have now revealed novel mechanisms and new therapeutic targets. Preclinical data have suggested that RNA dominance is responsive to therapeutic intervention and that DM therapy can be approached at several different levels...
April 1, 2017: Current Opinion in Genetics & Development
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