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Alberto Perez, Florian Sittel, Gerhard Stock, Ken A Dill
The molecular actions of proteins occur along reaction coordinates. Current computer methods have limited ability to explore them. We describe a fast protocol called MELD-path that: (1) efficiently samples relevant conformational states via MELD, an accelerator of Molecular Dynamics (MD), (2) seeds multiple short MD trajectories from MELD states, then (3) constructs Markov State Models (MSM) that give the routes and kinetics. We tested the method against extensive (multi μs) MD simulations of the right-handed- to left-handed-helix transition of a 9-mer peptide of AIB, the symmetry of which allows us to establish convergence...
March 16, 2018: Journal of Chemical Theory and Computation
Nicolas Daffern, Zhonglei Chen, Yongbo Zhang, Leslie Pick, Ishwar Radhakrishnan
The ligand-binding domains (LBD) of the NR5A subfamily of nuclear receptors activate transcription via ligand-dependent and ligand-independent mechanisms. The Drosophila Ftz-F1 receptor (NR5A3) belongs to the latter category and its ligand-independence is attributed to a short helical segment (6) within the protein that resides in the canonical ligand-binding pocket (LBP) in the crystalline state. Here, we show that the 6 helix is dynamic in solution when Ftz-F1 is bound to the LxxLL motif of its cofactor Ftz, undergoing motions on the fast (picosecond-nanosecond) as well as slow (microsecond-millisecond) timescales...
March 16, 2018: Biochemistry
Fırat Kurt, Ertugrul Filiz
Iron (Fe) is an essential element for plant life. Its deficiency impedes growth and development and excessive iron can cause the toxic effect via the Fenton reaction. Thus, plants have developed various mechanisms to acquire, distribute and utilize Fe for the maintenance of their iron homeostasis at cellular and systemic levels. A basic helix-loop-helix (bHLH) transcription factor family plays essential roles in many regulatory and development processes in plants. In this study, we aimed to understand the roles of bHLH38, bHLH39, bHLH100 and bHLH101 genes for Fe homeostasis in Arabidopsis, tomato, rice, soybean and maize species by using bioinformatics approaches...
March 15, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Lokesh K Narnoliya, Rajender S Sangwan, Sudhir P Singh
Rose-scented geranium (Pelargonium sp.) is widely known as aromatic and medicinal herb, accumulating specialized metabolites of high economic importance, such as essential oils, ascorbic acid, and tartaric acid. Ascorbic acid and tartaric acid are multifunctional metabolites of human value to be used as vital antioxidants and flavor enhancing agents in food products. No information is available related to the structural and functional properties of the enzymes involved in ascorbic acid and tartaric acid biosynthesis in rose-scented geranium...
March 15, 2018: Molecular Biology Reports
Jordi Grau, Cristina Renau, Ana B Caballero, Amparo Caubet, Marta Pockaj, Julia Lorenzo, Patrick Gamez
The [Cu(L)Cl2]2 and [Pt(L)Cl2] complexes were prepared from the simple Schiff-base ligand (E)-phenyl-N-((pyridin-2-yl)methylene)methanamine (L) and respectively, CuCl2 and cis-[PtCl2(DMSO)2]. DNA-interaction studies revealed that the copper complex most likely acts as a DNA cleaver whereas the platinum complex binds to the double helix. Remarkably, cell-viability experiments with HeLa, MCF7 and PC3 cells showed that [Cu(L)Cl2]2 is an efficient cytotoxic agent whereas [Pt(L)Cl2] is not toxic, illustrating the crucial role played by the nature of the metal ion in the corresponding biological activity...
March 16, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Sébastien Gillotin, John D Davies, Anna Philpott
The proneural transcription factor Ascl1 is a master regulator of neurogenesis, coordinating proliferation and differentiation in the central nervous system. While its expression is well characterised, post-translational regulation is much less well understood. Here we demonstrate that a population of chromatin-bound Ascl1 can be found associated with short chains of ubiquitin while cytoplasmic Ascl1 harbours much longer ubiquitin chains. Only cytoplasmic ubiquitylation targets Ascl1 for destruction, which occurs by conjugation of ubiquitin to lysines in the basic helix-loop-helix domain of Ascl1 and requires the E3 ligase Huwe1...
March 15, 2018: Scientific Reports
Elizabeth C Curran, Hui Wang, Thomas R Hinds, Ning Zheng, Edith H Wang
The general transcription factor IID (TFIID) is the first component of the preinitiation complex (PIC) to bind the core promoter of RNA polymerase II transcribed genes. Despite its critical role in protein-encoded gene expression, how TFIID engages promoter DNA remains elusive. We have previously revealed a winged-helix DNA-binding domain in the N-terminal region of the largest TFIID subunit, TAF1. Here, we report the identification of a second DNA-binding module in the C-terminal half of human TAF1, which is encoded by a previously uncharacterized conserved zinc knuckle domain...
March 15, 2018: Scientific Reports
Matthew V Helliwell, Yihong Zhang, Aziza El Harchi, Chunyun Du, Jules C Hancox, Christopher E Dempsey
Cardiac potassium channels encoded by human Ether-à-go-go Related Gene (hERG) are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug binding site of the hERG pore. hERG current (IhERG ) recorded at physiological temperature from HEK 293 cells was inhibited with an IC50 of 35...
March 15, 2018: Journal of Biological Chemistry
Sukhendu Mandal, Semanti Ghosh, Debabrata Sinha, Soham Seal, Avisek Mahapa, Soumitra Polley, Deeya Saha, Keya Sau, Angshuman Bagchi, Subrata Sau
SarA, a winged-helix DNA binding protein, is a global virulence regulator in Staphylococcus aureus. The putative DNA binding region of SarA is located between amino acid residues Leu 53 and Gln 97. Previous studies have demonstrated that residues at positions 84, 88, 89, and 90 are critical for its function. To precisely understand the roles of the DNA binding residues, we have investigated nine mutants of a recombinant SarA (rSarA) along with the rSarA mutants carrying mutations at the above four positions...
March 12, 2018: International Journal of Biological Macromolecules
So Young Kim, Sun-June Park, Kap Sung Oh
PURPOSE: With the aim of implementing good projection of the three-dimensional frame (auriculo-cephalic angle) and maintaining projection, a significant issue during the stage of auricular elevation for avoiding the potential for dislodging the cartilage blocks remains. Herein we present an innovative and technically simple method of transcutaneous fixation of the costal cartilage block during the stage of auricular elevation. MATERIALS AND METHODS: After elevation of ear frame from the basement, two suspension stitches on the surface of the elevated ear were used to fix the embedding cartilage block into the auriculo-cephalic sulcus at the upper (bifurcation point of the anti-helix where the inferior and superior crus meet to form the triangular fossa) and lower (projection point of the concha wall, parallel to the level of the tragus) ones...
February 2, 2018: Journal of Cranio-maxillo-facial Surgery
Daniel J Dennis, Sisu Han, Carol Schuurmans
The formation of functional neural circuits in the vertebrate central nervous system (CNS) requires that appropriate numbers of the correct types of neuronal and glial cells are generated in their proper places and times during development. In the embryonic CNS, multipotent progenitor cells first acquire regional identities, and then undergo precisely choreographed temporal identity transitions (i.e. time-dependent changes in their identity) that determine how many neuronal and glial cells of each type they will generate...
March 12, 2018: Brain Research
Annie Liu, Alexis Botkin, Christian Murray, David Goldstein, Stefan O P Hofer, Nowell Solish, Jessica Kitchen, An-Wen Chan
BACKGROUND: Lentigo maligna is an in situ form of cutaneous melanoma that commonly arises on the head and neck. Various surgical and nonsurgical treatment options are available but no randomized trials exist to guide practice. OBJECTIVE: To determine the current treatment practices for lentigo maligna of the head and neck in Ontario, Canada. MATERIALS AND METHODS: Cross-sectional survey of dermatologists, plastic surgeons, and head and neck surgeons...
March 13, 2018: Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]
Giacomo Reina, Ngoc Do Quyen Chau, Yuta Nishina, Alberto Bianco
Several studies have demonstrated the ability of graphene oxide (GO) to efficiently adsorb small-interfering RNA (siRNA) on its surface and to transport it into cells. However, studies on whether and how siRNA interacts with GO are still inconclusive. In this context, understanding the interaction between GO and siRNA is fundamental to design new efficient gene silencing tools. In this work, the interactions between GO and siRNA molecules were systematically investigated. We focused on how the GO size, oxygenated groups present on the surface and chemical functionalization affect the double helix siRNA structure, using gel electrophoresis, UV-Vis spectroscopy, fluorescence resonance energy transfer (FRET) and circular dichroism (CD)...
March 15, 2018: Nanoscale
Krzysztof B Beć, Yusuke Morisawa, Kenta Kobashi, Justyna Grabska, Ichiro Tanabe, Erika Tanimura, Harumi Sato, Marek J Wójcik, Yukihiro Ozaki
We investigated the surface (<50 nm) of poly(3-hydroxybutyrate) (PHB) and its nanocomposite with graphene by attenuated total reflection far- and deep-ultraviolet (ATR-FUV-DUV; 145-300 nm; 8.55-4.13 eV) spectroscopy and quantum mechanical calculations. The major absorption of polymers occurs in FUV and is related to Rydberg transitions. ATR-FUV-DUV spectroscopy allows for direct measurements of these transitions in the solid phase. Using ATR-FUV-DUV spectroscopy, periodic density functional theory (DFT) and time-dependent DFT (TD-DFT), we explained the origins of the FUV-DUV absorption of PHB and provided insights into structural changes of PHB which occur upon formation of a graphene nanocomposite and upon heating of the pure polymer...
March 15, 2018: Physical Chemistry Chemical Physics: PCCP
Yoshinori Hirano, Yu Amano, Shigenobu Yonemura, Toshio Hakoshima
Mechanotransduction by α-catenin facilitates the force-dependent development of adherens junctions (AJs) by recruiting vinculin to reinforce actin anchoring of AJs. The α-catenin mechanotransducing action is facilitated by its force-sensing device region that autoinhibits the vinculin-binding site 1 (VBS1). Here, we report the high-resolution structure of the force-sensing device region of α-catenin, which shows the autoinhibited form comprised of helix bundles E, F and G. The cryptic VBS1 is embedded into helix bundle E stabilized by direct interactions with the autoinhibitory region forming helix bundles F and G...
March 15, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Meng-Ting Li, Ning Kong, Ya-Qian Lan, Zhong-Min Su
We utilise the dual synthesis strategy in terms of bimetallic inorganic building blocks and sulfur containing organic ligand. A novel sulfur-containing bimetallic metal organic framework (Fe2 Co-TPDC) with two types of 4-fold meso-helical structures has been successfully synthesized. Benefitting from the uniform distribution of active sulfur sites and the structural stability of the mixed-metallic method, Fe2 Co-TPDC can efficiently prevent a shuttle behavior of sulfur and endow a commendable specific capacity...
March 15, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Yi-Shu Huang, Nien-Yi Chiang, Gin-Wen Chang, Hsi-Hsien Lin
The evolutionarily conserved adhesion G protein-coupled receptors (aGPCRs) play critical roles in biological processes as diverse as brain development, cell polarity and innate immune functions. A defining feature of aGPCRs is the GPCR autoproteolysis inducing (GAIN) domain capable of self-catalytic cleavage, resulting in the generation of an extracellular N-terminal fragment (NTF) and a seven-transmembrane C-terminal fragment (CTF) involved in the cellular adhesion and signaling functions, respectively. Interestingly, two different NTF subtypes have previously been identified, namely an NTF that couples non-covalently with the CTF and a membrane-associated NTF that tethers on cell surface independently...
March 14, 2018: Scientific Reports
Megan Sjodt, Ramsay Macdonald, Joanna D Marshall, Joseph Clayton, John S Olson, Martin L Phillips, David A Gell, Jeff Wereszczynski, Robert T Clubb
Staphylococcus aureus is a leading cause of life-threatening infections in the United States. It actively acquires the essential nutrient iron from human hemoglobin (Hb) using the iron-regulated surface-determinant (Isd) system. This process is initiated when the closely related bacterial IsdB and IsdH receptors bind to Hb and extract its hemin through a conserved tri-domain unit that contains two NEAr iron Transporter (NEAT) domains that are connected by a helical linker domain. Previously, we demonstrated that the tri-domain unit within IsdH (IsdHN2N3 ) triggers hemin release by distorting Hb's F-helix...
March 14, 2018: Journal of Biological Chemistry
Neeraja Purandare, Mallika Somayajulu, Maik Hüttemann, Lawrence I Grossman, Siddhesh Aras
Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX9C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus. We show that CHCHD10 co-purifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL proto-oncogene 2, non-receptor tyrosine kinase [ABL2])...
March 14, 2018: Journal of Biological Chemistry
Huanchen Wang, Chunfang Gu, Ronda J Rolfes, Henning J Jessen, Stephen B Shears
Inositol pyrophosphates (PP-InsPs) are 'energetic' intracellular signals that are ubiquitous in animals, plant and fungi; structural and biochemical characterization of PP-InsP metabolic enzymes provides insight into their evolution, reaction mechanisms, and regulation. Here, we describe the 2.35 Å resolution structure of the catalytic core of Siw14, a 5-PP-InsP phosphatase from Saccharomyces cerevisiae, and a member of the protein tyrosinephosphatase (PTP) superfamily. Conclusions that we derive from structural data are supported by extensive site-directed mutagenesis and kinetic analyses, thereby attributing new functional significance to several key residues...
March 14, 2018: Journal of Biological Chemistry
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