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https://www.readbyqxmd.com/read/28104818/structure-and-activation-of-c1-the-complex-initiating-the-classical-pathway-of-the-complement-cascade
#1
Simon A Mortensen, Bjoern Sander, Rasmus K Jensen, Jan Skov Pedersen, Monika M Golas, Jens C Jensenius, Annette G Hansen, Steffen Thiel, Gregers R Andersen
The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r2s2, to a variety of activators presenting specific molecular patterns such as IgG- and IgM-containing immune complexes. A canonical model entails a C1r2s2 with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator...
January 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28101858/coiled-coil-design-updated-and-upgraded
#2
Derek N Woolfson
α-Helical coiled coils are ubiquitous protein-folding and protein-interaction domains in which two or more α-helical chains come together to form bundles. Through a combination of bioinformatics analysis of many thousands of natural coiled-coil sequences and structures, plus empirical protein engineering and design studies, there is now a deep understanding of the sequence-to-structure relationships for this class of protein architecture. This has led to considerable success in rational design and what might be termed in biro de novo design of simple coiled coils, which include homo- and hetero-meric parallel dimers, trimers and tetramers...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28098784/fused-ring-oxazolopyrrolopyridopyrimidine-systems-with-gram-negative-activity
#3
Yiyuan Chen, Jonathan G Moloney, Kirsten E Christensen, Mark G Moloney
Fused polyheterocyclic derivatives are available by annulation of a tetramate scaffold, and been shown to have antibacterial activity against a Gram-negative, but not a Gram-positive, bacterial strain. While the activity is not potent, these systems are structurally novel showing, in particular, a high level of polarity, and offer potential for the optimization of antibacterial activity.
January 13, 2017: Antibiotics
https://www.readbyqxmd.com/read/28098779/unravelling-the-diversity-of-the-cyclopiazonic-acid-family-of-mycotoxins-in-aspergillus-flavus-by-uhplc-triple-tof-hrms
#4
Valdet Uka, Geromy G Moore, Natalia Arroyo-Manzanares, Dashnor Nebija, Sarah De Saeger, José Diana Di Mavungu
Cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) is an indole-hydrindane-tetramic acid neurotoxin produced by various fungal species, including the notorious food and feed contaminant Aspergillus flavus. Despite its discovery in A. flavus cultures approximately 40 years ago, its contribution to the A. flavus mycotoxin burden is consistently minimized by our focus on the more potent carcinogenic aflatoxins also produced by this fungus. Here, we report the screening and identification of several CPA-type alkaloids not previously found in A...
January 13, 2017: Toxins
https://www.readbyqxmd.com/read/28098172/structural-diversity-of-anti-pancreatic-cancer-capsimycins-identified-in-mangrove-derived-streptomyces-xiamenensis-318-and-post-modification-via-a-novel-cytochrome-p450-monooxygenase
#5
He-Lin Yu, Shu-Heng Jiang, Xu-Liang Bu, Jia-Hua Wang, Jing-Yi Weng, Xiao-Mei Yang, Kun-Yan He, Zhi-Gang Zhang, Ping Ao, Jun Xu, Min-Juan Xu
Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds-ikarugamycin (1), capsimycin (2) and capsimycin B (3)-two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096372/helical-structure-stability-and-dynamics-in-human-apolipoprotein-e3-and-e4-by-hydrogen-exchange-and-mass-spectrometry
#6
Palaniappan S Chetty, Leland Mayne, Sissel Lund-Katz, S Walter Englander, Michael C Phillips
Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen-deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28093848/one-mutation-two-distinct-disease-variants-unravelling-the-impact-of-transthyretin-amyloid-fibril-composition
#7
REVIEW
O B Suhr, E Lundgren, P Westermark
Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR...
January 17, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28093469/assembly-of-the%C3%A2-elongated-collagen-prolyl-4-hydroxylase-%C3%AE-2%C3%AE-2-heterotetramer%C3%A2-around-a-central-%C3%AE-2-dimer
#8
Kristian Koski, Jothi Anantharajan, Petri Kursula, Prathusha Dhavala, Abhinandan Venkatesha Murthy, Ulrich Bergmann, Johanna Myllyharju, Rik K Wierenga
COLLAGEN PROLYL 4-HYDROXYLASE C-P4H, AN Α2Β2 HETEROTETRAMER, IS A CRUCIAL ENZYME FOR COLLAGEN SYNTHESIS THE Α SUBUNIT CONSISTS OF AN N TERMINAL DIMERIZATION DOMAIN, A CENTRAL PEPTIDE-SUBSTRATE-BINDING PSB DOMAIN, AND A C TERMINAL CATALYTIC CAT DOMAIN THE Β SUBUNIT ALSO KNOWN AS PROTEIN DISULFIDE ISOMERASE PDI ACTS AS A CHAPERONE, STABILIZING THE FUNCTIONAL CONFORMATION OF C-P4H C-P4H HAS BEEN STUDIED FOR DECADES, BUT ITS STRUCTURE HAS REMAINED ELUSIVE HERE, WE PRESENT : A THREE-DIMENSIONAL SMALL-ANGLE X-RAY SCATTERING SAXS MODEL OF THE ENTIRE HUMAN C-P4H-I HETEROTETRAMER C-P4H IS AN ELONGATED, BILOBAL, SYMMETRIC MOLECULE WITH A LENGTH OF 290 Å THE DIMERIZATION DOMAINS FROM THE TWO A SUBUNITS FORM A PROTEIN-PROTEIN DIMER INTERFACE, ASSEMBLED AROUND THE CENTRAL ANTIPARALLEL COILED-COIL INTERFACE OF THEIR N TERMINAL Α HELICES THIS REGION FORMS A THIN WAIST IN THE BILOBAL TETRAMER THE TWO PSB/CAT UNITS, EACH COMPLEXED WITH A PDI/Β SUBUNIT, FORM TWO BULKY LOBES POINTING OUTWARD FROM THIS WAIST REGION, SUCH THAT THE PDI/Β SUBUNITS LOCATE AT THE FAR ENDS OF THE ΒΑΑΒ COMPLEX THE PDI/Β SUBUNIT INTERACTS EXTENSIVELY WITH THE CAT DOMAIN THE ASYMMETRIC SHAPE OF TWO TRUNCATED C-P4H-I VARIANTS, ALSO CHARACTERIZED IN THIS STUDY, AGREES WITH THIS ASSEMBLY FURTHERMORE, DATA FROM THESE TRUNCATED VARIANTS SHOW THAT DIMERIZATION BETWEEN THE A SUBUNITS HAS AN IMPORTANT ROLE IN ACHIEVING THE CORRECT PSB-CAT ASSEMBLY COMPETENT FOR CATALYTIC ACTIVITY KINETIC ASSAYS WITH VARIOUS PROLINE-RICH PEPTIDE SUBSTRATES AND INHIBITORS SUGGEST THAT IN THE COMPETENT ASSEMBLY, THE PSB DOMAIN BINDS TO THE PROCOLLAGEN SUBSTRATE DOWNSTREAM FROM THE CAT DOMAIN...
January 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28093446/tumor-infiltrating-merkel-cell-polyomavirus-specific-t-cells-are-diverse-and-associated-with-improved-patient-survival
#9
Natalie J Miller, Candice D Church, Lichun Dong, David Crispin, Matthew P Fitzgibbon, Kristina Lachance, Lichen Jing, Michi Shinohara, Ioannis Gavvovidis, Gerald Willimsky, Martin McIntosh, Thomas Blankenstein, David M Koelle, Paul Nghiem
Tumor-infiltrating CD8(+) T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8(+) T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, "KLL") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer(+) CD8(+) T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry...
January 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28089597/magnesium-and-calcium-ions-differentially-affect-human-serine-racemase-activity-and-modulate-its-quaternary-equilibrium-toward-a-tetrameric-form
#10
Stefano Bruno, Marilena Margiotta, Francesco Marchesani, Gianluca Paredi, Valentina Orlandi, Serena Faggiano, Luca Ronda, Barbara Campanini, Andrea Mozzarelli
Serine racemase is the pyridoxal 5'-phosphate dependent enzyme that catalyzes both production and catabolism of d-serine, a co-agonist of the NMDA glutamate receptors. Mg(2+), or, alternatively, Ca(2+), activate human serine racemase by binding both at a specific site and - as ATP-metal complexes - at a distinct ATP binding site. We show that Mg(2+) and Ca(2+) bind at the metal binding site with a 4.5-fold difference in affinity, producing a similar thermal stabilization and partially shifting the dimer-tetramer equilibrium in favour of the latter...
January 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28087462/impact-of-disease-linked-mutations-targeting-the-oligomerization-interfaces-of-aldehyde-dehydrogenase-7a1
#11
David A Korasick, John J Tanner, Michael T Henzl
Aldehyde dehydrogenase 7A1 (ALDH7A1) is involved in lysine catabolism, catalyzing the oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Certain mutations in the ALDH7A1 gene, which are presumed to reduce catalytic activity, cause an autosomal recessive seizure disorder known as pyridoxine-dependent epilepsy (PDE). Although the genetic association between ALDH7A1 and PDE is well established, little is known about the impact of PDE-mutations on the structure and catalytic function of the enzyme. Herein we report the first study of the molecular consequences of PDE mutations using purified ALDH7A1 variants...
January 10, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28080033/solvent-templated-folding-of-perylene-bisimide-macrocycles-into-coiled-double-string-ropes-with-solvent-sensitive-optical-signatures
#12
Peter Spenst, Ryan M Young, Brian T Phelan, Michel Keller, Jakub Dostál, Tobias Brixner, Michael R Wasielewski, Frank Würthner
A series of semi-rigid perylene bisimide (PBI) macrocycles with varied ring size containing two to nine PBI chromophores were synthesized in a one-pot reaction and their photophysical properties were characterized by fluorescence, steady-state and transient absorption spectroscopy as well as femtosecond stimulated Raman spectroscopy. These macrocycles show solvent-dependent conformational equilibria and excited-state properties. In dichloromethane the macrocycles prevail in wide-stretched conformations and exhibit upon photoexcitation symmetry-breaking charge separation followed by charge recombination to triplet states, which photosensitize singlet oxygen formation...
January 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28077659/hiv-controllers-exhibit-enhanced-frequencies-of-mhc-class-ii-tetramer-gag-specific-cd4-t-cells-in-chronic-clade-c-hiv-1-infection
#13
Faatima Laher, Srinika Ranasinghe, Filippos Porichis, Nikoshia Mewalal, Karyn Pretorius, Nasreen Ismail, Søren Buus, Anette Stryhn, Mary Carrington, Bruce D Walker, Thumbi Ndung'u, Zaza M Ndhlovu
: Immune control of viral infections is heavily dependent on helper CD4(+) T cell function. However, understanding the contribution of HIV-specific CD4(+) T cell responses to immune protection against HIV-1, particularly in clade C infection remains incomplete. Recently, MHC class II tetramers have emerged as a powerful tool for interrogating antigen specific CD4(+) T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4(+) T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to viral load of HIV-specific CD4(+) T cell responses in a cohort of untreated HIV clade C infected persons...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28076788/dynamin-2-stabilizes-the-hiv-1-fusion-pore-with-a-low-oligomeric-state
#14
Daniel M Jones, Luis A Alvarez, Rory Nolan, Margarita Ferriz, Raquel Sainz Urruela, Xènia Massana-Muñoz, Hila Novak-Kotzer, Michael L Dustin, Sergi Padilla-Parra
One of the key research areas surrounding HIV-1 concerns the regulation of the fusion event that occurs between the virus particle and the host cell during entry. Even if it is universally accepted that the large GTPase dynamin-2 is important during HIV-1 entry, its exact role during the first steps of HIV-1 infection is not well characterized. Here, we have utilized a multidisciplinary approach to study the DNM2 role during fusion of HIV-1 in primary resting CD4 T and TZM-bl cells. We have combined advanced light microscopy and functional cell-based assays to experimentally assess the role of dynamin-2 during these processes...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28074902/a-reduced-mechanical-model-for-camp-modulated-gating-in-hcn-channels
#15
Stephanie Weißgraeber, Andrea Saponaro, Gerhard Thiel, Kay Hamacher
We developed an in silico mechanical model to analyze the process of cAMP-induced conformational modulations in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which conduct cations across the membrane of mammalian heart and brain cells. The structural analysis reveals a quaternary twist in the cytosolic parts of the four subunits in the channel tetramer. This motion augments the intrinsic dynamics of the very same protein structure. The pronounced differences between the cAMP bound and unbound form include a mutual interaction between the C-linker of the cyclic nucleotide binding domain (CNBD) and the linker between the S4 and S5 transmembrane domain of the channel...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28074868/nucleoplasmin-like-domain-of-fkbp39-from-drosophila-melanogaster-forms-a-tetramer-with-partly-disordered-tentacle-like-c-terminal-segments
#16
Małgorzata Kozłowska, Aneta Tarczewska, Michał Jakób, Dominika Bystranowska, Michał Taube, Maciej Kozak, Mariusz Czarnocki-Cieciura, Andrzej Dziembowski, Marek Orłowski, Katarzyna Tkocz, Andrzej Ożyhar
Nucleoplasmins are a nuclear chaperone family defined by the presence of a highly conserved N-terminal core domain. X-ray crystallographic studies of isolated nucleoplasmin core domains revealed a β-propeller structure consisting of a set of five monomers that together form a stable pentamer. Recent studies on isolated N-terminal domains from Drosophila 39-kDa FK506-binding protein (FKBP39) and from other chromatin-associated proteins showed analogous, nucleoplasmin-like (NPL) pentameric structures. Here, we report that the NPL domain of the full-length FKBP39 does not form pentameric complexes...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28071757/new-insights-into-the-gins-complex-explain-the-controversy-between-existing-structural-models
#17
Marta Carroni, Matteo De March, Barbara Medagli, Ivet Krastanova, Ian A Taylor, Heinz Amenitsch, Hiroyuchi Araki, Francesca M Pisani, Ardan Patwardhan, Silvia Onesti
GINS is a key component of eukaryotic replicative forks and is composed of four subunits (Sld5, Psf1, Psf2, Psf3). To explain the discrepancy between structural data from crystallography and electron microscopy (EM), we show that GINS is a compact tetramer in solution as observed in crystal structures, but also forms a double-tetrameric population, detectable by EM. This may represent an intermediate step towards the assembly of two replicative helicase complexes at origins, moving in opposite directions within the replication bubble...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28070655/synthetic-introns-help-identify-sequences-in-the-5-utr-intron-of-the-glycine-max-polyubiquitin-gmubi-promoter-that-give-increased-promoter-activity
#18
Trudi N L Grant, Carola M De La Torre, Ning Zhang, John J Finer
Specific sequences within the leader intron of a soybean polyubiquitin gene stimulated gene expression when placed either within a synthetic intron or upstream of a core promoter. The intron in the 5' untranslated region of the soybean polyubiquitin promoter, Gmubi, seems to contribute to the high activity of this promoter. To identify the stimulatory sequences within the intron, ten different sequential intronic sequences of 40 nt were isolated, cloned as tetrameric repeats and placed upstream of a minimal cauliflower mosaic virus 35S (35S) core promoter, which was used to control expression of the green fluorescent protein...
January 9, 2017: Planta
https://www.readbyqxmd.com/read/28067444/irreversible-conversion-of-a-water-ethanol-solution-into-an-organized-two-dimensional-network-of-alternating-supramolecular-units-in-a-hydrophobic-zeolite-under-pressure
#19
Rossella Arletti, Ettore Fois, Lara Gigli, Giovanna Vezzalini, Simona Quartieri, Gloria Tabacchi
Turning disorder into organization is a key issue in science. By making use of X-ray powder diffraction and modeling studies, we show herein that high pressures in combination with the shape and space constraints of the hydrophobic all-silica zeolite ferrierite separate an ethanol-water liquid mixture into ethanol dimer wires and water tetramer squares. The confined supramolecular blocks alternate in a binary two-dimensional (2D) architecture that remains stable upon complete pressure release. These results support the combined use of high pressures and porous networks as a viable strategy for driving the organization of molecules or nano-objects towards complex, pre-defined patterns relevant for the realization of novel functional nanocomposites...
January 9, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28066922/x-ray-crystal-structure-of-the-n-terminal-region-of-moloney-murine-leukemia-virus-integrase-and-its-implications-for-viral-dna-recognition
#20
Rongjin Guan, Sriram Aiyer, Marie L Cote, Rong Xiao, Mei Jiang, Thomas B Acton, Monica J Roth, Gaetano T Montelione
The retroviral integrase (IN) carries out the integration of a dsDNA copy of the viral genome into the host DNA, an essential step for viral replication. All IN proteins have three general domains, the N-terminal domain (NTD), the catalytic core domain (CCD), and the C-terminal domain (CTD). The NTD includes an HHCC zinc finger-like motif, which is conserved in all retroviral IN proteins. Two crystal structures of Moloney murine leukemia virus (M-MuLV) IN N-terminal region (NTR) constructs that both include an N-terminal extension domain (NED, residues 1-44) and an HHCC zinc-finger NTD (residues 45-105), in two crystal forms are reported...
January 9, 2017: Proteins
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