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Journal of Molecular Biology

Sella Kim, Ji-Hye Lee, Jong Hyeon Seok, Yi-Ho Park, Sang Won Jung, Art E Cho, Cheolju Lee, Mi Sook Chung, Kyung Hyun Kim
Iron and oxygen chemistry is mediated by iron proteins for many biological functions. Carboxylate-bridged diiron enzymes including ferritin have in common the mechanism of oxygen activation via peroxodiferric intermediates. However, the route for iron uptake and the structural identification of intermediates still remain incomplete. The 4-fold symmetry channel of Helicobacter pylori ferritin (Hpf) was previously proposed as the iron uptake route in eubacteria, but the amino acid residues at the 4-fold channel are not highly conserved...
October 21, 2016: Journal of Molecular Biology
Matthias Groh, Laura Oana Albulescu, Agnese Cristini, Natalia Gromak
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia, Fragile X syndrome) and cancer. Currently it is unclear which mechanisms cause R-loops structures to become pathogenic. The RNA/DNA helicase Senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4)...
October 19, 2016: Journal of Molecular Biology
Christine Yueh, David R Hall, Bing Xia, Dzmitry Padhorny, Dima Kozakov, Sandor Vajda
ClusPro-DC ( implements a straightforward approach to the discrimination between crystallographic and biological dimers by docking the two subunits to exhaustively sample the interaction energy landscape. If a substantial number of low energy docked poses cluster in a narrow vicinity of the native structure of the dimer, then one can assume that there is a well-defined free energy well around the native state, which makes the interaction stable. In contrast, if the interaction sites in the docked poses do not form a large enough cluster around the native structure, then it is unlikely that the subunits form a stable biological dimer...
October 19, 2016: Journal of Molecular Biology
William R Taylor
No abstract text is available yet for this article.
October 19, 2016: Journal of Molecular Biology
Russell T Chan, Kevin S Keating, Michaela C Go, Navtej Toor
Large RNAs often utilize GNRA tetraloops as structural elements to stabilize the overall tertiary fold. These tetraloop-receptor (TR) interactions have a conserved geometry in which the tetraloop docks into the receptor at an angle of ~15° from the helix containing the receptor. Here, we show that the conserved GUAAY pentaloop found in domain III of group IIB1 introns participates in a novel class of RNA tertiary interaction with a geometry and mode of binding that are significantly different from that found in GNRA TR interactions...
October 19, 2016: Journal of Molecular Biology
Dennis Walczyk, Markus Gößringer, Walter Rossmanith, Timofei S Zatsepin, Tatiana S Oretskaya, Roland K Hartmann
Ribonuclease P (RNase P) is the enzyme that endonucleolytically removes 5'-precursor sequences from tRNA transcripts in all domains of life. RNase P activities are either ribonucleoprotein (RNP) or protein-only (PRORP) enzymes, raising the question about the mechanistic strategies utilized by these architecturally different enzyme classes to catalyze the same type of reaction. Here we analyzed the kinetics and cleavage-site selection by PRORP3 from Arabidopsis thaliana (AtPRORP3) using precursor tRNAs (pre-tRNAs) with individual modifications at the canonical cleavage site, either Rp- or Sp-phosphorothioate, or 2'-deoxy, 2'-fluoro, 2'-amino or 2'-O-methyl substitutions...
October 18, 2016: Journal of Molecular Biology
Deepika Jaiswal, Rashi Turniansky, Erin M Green
When yeast cells are challenged by a fluctuating environment, signaling networks activate differentiation programs that promote their individual or collective survival. These programs include the initiation of meiotic sporulation, the formation of filamentous growth structures, and the activation of programmed cell death pathways. The establishment and maintenance of these distinct cell fates are driven by massive gene expression programs that promote the necessary changes in morphology and physiology. While these genomic reprogramming events depend on a specialized network of transcription factors, a diverse set of chromatin regulators, including histone-modifying enzymes, chromatin remodelers, and histone variants, also play essential roles...
October 18, 2016: Journal of Molecular Biology
Jessica M Wilson, Jeremy W Prokop, Ellen Lorimer, Elizabeth Ntantie, Carol L Williams
Two isoforms of the small GTPase Rap1, Rap1A and Rap1B, participate in cell adhesion; Rap1A promotes steady state adhesion, while Rap1B regulates dynamic changes in cell adhesion. These events depend on the prenylation of Rap1, which promotes its membrane localization. Here, we identify previously unsuspected differences in the regulation of prenylation of Rap1A versus Rap1B, due in part to their different phosphorylation-dependent interactions with the chaperone protein SmgGDS-607. Previous studies indicate that activation of Gαs protein-coupled receptors (GPCRs) phosphorylates S-179 and S-180 in the polybasic region (PBR) of Rap1B, which inhibits Rap1B binding to SmgGDS-607 and diminishes Rap1B prenylation and membrane localization...
October 16, 2016: Journal of Molecular Biology
Patricia Perez-Arnaiz, Daniel L Kaplan
Mcm10 is an essential protein that functions to initiate DNA replication after the formation of the replication fork helicase. In this manuscript, we identified a budding yeast Mcm10 mutant (Mcm10-m2,3,4) that is defective in DNA binding in vitro. Moreover, this Mcm10-m2,3,4 mutant does not stimulate the phosphorylation of Mcm2 by DDK in vitro. When we expressed wild-type levels of mcm10-m2,3,4 in budding yeast cells, we observed a severe growth defect and substantially decreased DNA replication. We also observed a substantially reduced RPA-ChIP signal at origins of replication, reduced levels of DDK-phosphorylated-Mcm2 and diminished GINS association with Mcm2-7 in vivo...
October 14, 2016: Journal of Molecular Biology
Rane A Harrison, Jia Lu, Martin Carrasco, John Hunter, Anuj Manandhar, Sudershan Gondi, Kenneth D Westover, John R Engen
Structural dynamics of Ras proteins contribute to their activity in signal transduction cascades. Directly targeting Ras proteins with small molecules may rely on movement of a conserved structural motif, switch II. To understand Ras signaling and advance Ras targeting strategies, experimental methods to measure Ras dynamics are required. Here we demonstrate the utility of hydrogen-deuterium exchange mass spectrometry to measure Ras dynamics by studying representatives from two branches of the Ras superfamily, Ras and Rho...
October 14, 2016: Journal of Molecular Biology
P Zhang, L Tao, X Zeng, C Qin, S Y Chen, F Zhu, S Y Yang, Z R Li, W P Chen, Y Z Chen
The studies of biological, disease and pharmacological networks are facilitated by the systems-level investigations using computational tools. In particular, the network descriptors developed in other disciplines have found increasing applications in the study of the protein, gene regulatory, metabolic, disease, and drug-targeted networks. Facilities are provided by the public web-servers for computing network descriptors, but many descriptors are not covered including those used or useful for biological studies...
October 11, 2016: Journal of Molecular Biology
M Wassef, R Margueron
Genome sequencing of large cohorts of tumors has revealed that mutations in genes encoding chromatin regulators are frequent in cancer. However, the precise contribution of these mutations to tumor development often remains elusive. Here, we review the current knowledge concerning the alterations of the Polycomb machinery in cancer, with a particular focus on the Polycomb repressive complex 2 (PRC2), a key chromatin modifier involved in the maintenance of transcriptional silencing. A broad variety of alterations can impair PRC2 activity; yet, overall, only one type of alteration is found in a given class of tumor...
October 12, 2016: Journal of Molecular Biology
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 11, 2016: Journal of Molecular Biology
Alexander R Siegel, David E Wemmer
Bacterial sigma factors are subunits of RNA polymerase that direct the holoenzyme to specific sets of promoters in the genome, and are a central element of regulating transcription. Most polymerase holoenzymes open the promoter and initiate transcription rapidly after binding. However, polymerase containing members of the σ(54) family must be acted on by a transcriptional activator before DNA opening and initiation occur. A key domain in these transcriptional activators forms a hexameric AAA+ ATPase that acts through conformational changes brought on by ATP hydrolysis...
October 9, 2016: Journal of Molecular Biology
Maggy Hologne, François-Xavier Cantrelle, Gwladys Riviere, Florence Guillière, Xavier Trivelli, Olivier Walker
AMSH is one of the deubiquitinating enzymes associated in the regulation of endocytic cargo trafficking. It shows an exquisite selectivity for Lys63-linked polyubiquitin chains that are the main chains involved in cargo sorting. The first step requires the ESCRT-0 complex that comprises the STAM and Hrs proteins. Previous studies have shown that the presence of the STAM protein increases the efficiency of Lys63-linked polyubiquitin chain cleavage by AMSH, one of the deubiquitinating enzyme involved in lysosomal degradation...
October 7, 2016: Journal of Molecular Biology
Tommaso Moschetti, Timothy Sharpe, Gerhard Fischer, May E Marsh, HongKin Ng, Matthew Morgan, Duncan Scott, Tom L Blundell, Ashok Venkitaraman, John Skidmore, Chris Abell, Marko Hyvönen
Protein-protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based drug discovery approaches to tackle PPIs are often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering to 'humanise' thermophilic archeal surrogate proteins as targets for small molecule inhibitor discovery, and exemplify this approach in the development of inhibitors against the PPI between the recombinase RAD51 and tumour suppressor BRCA2...
October 7, 2016: Journal of Molecular Biology
Célia V Romão, João B Vicente, Patrícia T Borges, Bruno L Victor, Pedro Lamosa, Elisio Silva, Luís Pereira, Tiago M Bandeiras, Cláudio M Soares, Maria A Carrondo, David Turner, Miguel Teixeira, Carlos Frazão
Flavodiiron proteins (FDPs) are present in organisms from all domains of life and have been described so far to be involved in the detoxification of oxygen or nitric oxide, acting as O2 and/or NO reductases. The Escherichia coli FDP, named flavorubredoxin (FlRd) is the most extensively studied FDP. Biochemical and in vivo studies revealed that FlRd is involved in NO detoxification, as part of the bacterial defense mechanisms against reactive nitrogen species. E. coli FlRd has a clear preference for NO as substrate in vitro, exhibiting a very low reactivity towards O2...
October 7, 2016: Journal of Molecular Biology
Tomáš Kroupa, Hana Langerová, Michal Doležal, Jan Prchal, Vojtěch Spiwok, Eric Hunter, Michaela Rumlová, Richard Hrabal, Tomáš Ruml
Matrix proteins play a key role in the transport of retroviral proteins inside infected cells and in the interaction with cellular membranes. In most retroviruses, retroviral matrix proteins are N-terminally myristoylated. This modification serves as a membrane targeting signal and also as an anchor for the membrane interaction. The aim of this work was to characterize interactions anchoring retroviral matrix protein at the plasma membrane of infected cell. To address this issue, we compared the structures and membrane affinity of the Mason-Pfizer monkey virus (M-PMV) wild-type matrix protein with its two budding deficient double mutants, i...
October 7, 2016: Journal of Molecular Biology
Di Zhang, Alexander Wlodawer, Jacek Lubkowski
The crystal structure of a construct consisting of the FERM and SH2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of the interferon-λ receptor 1 (IFNLR1) has been determined at the nominal resolution of 2.1Å. In this structure, the receptor peptide forms an 85-Å-long extended chain, in which both the previously identified box1 and box2 regions bind simultaneously to the FERM and SH2-like domains of JAK1. Both domains of JAK1 are generally well ordered, with regions not seen in the crystal structure limited to loops located away from the receptor-binding regions...
October 7, 2016: Journal of Molecular Biology
Annika Ciragan, A Sesilja Aranko, Igor Tascon, Hideo Iwaï
Intervening protein sequences (inteins) from extremely halophilic haloarchaea can be inactive under low salinity but could be activated by increasing salt contents to a specific concentration for each intein. The halo-obligatory inteins confer high solubility under both low and high salinity conditions. We showed the broad utility of salt-dependent protein splicing in cis and trans by demonstrating backbone cyclization, self-cleavage for purification, and scarless protein ligation for segmental isotopic labeling...
October 6, 2016: Journal of Molecular Biology
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