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Journal of Molecular Biology

Dylan J Taatjes
No abstract text is available yet for this article.
July 14, 2017: Journal of Molecular Biology
Muhammad Abid Sheikh, Yousra Saeed Malik, Xiaojuan Zhu
In a previous study, we identified several novel targets of Dnmt3b using a chromatin library from RA treated P19 cells. The present study describes the regulation of expression and function of Chk2 which was one of the target genes of Dnmt3b. ChIP followed by quantitative PCR analysis showed that recruitment of Dnmt3b on Chk2 promoter is induced following RA treatment of P19 cells. Both BGS and COBRA analysis showed that the methylation level of Chk2 promoter is progressively increased during RA induced neuronal differentiation of P19 cells...
July 13, 2017: Journal of Molecular Biology
John A Hammond, Li Zhou, Rajan Lamichhane, Hui-Yi Chu, David P Millar, Larry Gerace, James R Williamson
HIV-1 requires a specialized nuclear export pathway to transport unspliced and partially spliced viral transcripts to the cytoplasm. Central to this pathway is the viral protein Rev, which binds to the Rev response element in stem IIB located on unspliced viral transcripts and subsequently oligomerizes in a cooperative manner. Previous work identified a number of cellular DEAD-box helicases as in vivo binding partners of Rev, and siRNA experiments indicated a functional role for many in the HIV replication cycle...
July 10, 2017: Journal of Molecular Biology
Fan Wu, Gaojie Song, Chris de Graaf, Raymond C Stevens
G protein-coupled proteins (GPCRs) are the largest family of cell surface receptors and are important human drug targets. Of the 826 human GPCRs, 118 of them recognize endogenous peptide or protein ligands, and 30 of the 118 are targeted by approved drug molecules, including the very high profile class B glucagon-like peptide 1 receptor (GLP-1R). In this review, we analyze the 21 experimentally determined three-dimensional structures of the known peptide-binding GPCRs in relation to the endogenous peptides and drug molecules that modulate their cell signaling processes...
July 10, 2017: Journal of Molecular Biology
Mary L Hasek, Joshua B Maurer, Roger W Hendrix, Robert L Duda
Viruses build icosahedral capsids of specific size and shape by regulating the spatial arrangement of the hexameric and pentameric protein capsomers in the growing shell during assembly. In the T=7 capsids of E. coli bacteriophage HK97 and other phages, sixty capsomers are hexons, while the rest are pentons that are correctly positioned during assembly. Assembly of the HK97 capsid to the correct size and shape has been shown to depend on specific ionic contacts between capsomers. We now describe additional ionic interactions within capsomers that also regulate assembly...
July 10, 2017: Journal of Molecular Biology
Katie L Stewart, Eleri Hughes, Edwin A Yates, David A Middleton, Sheena E Radford
The Aβ peptide forms extracellular plaques associated with Alzheimer's disease. In addition to protein fibrils, amyloid plaques also contain non-proteinaceous components, including glycosaminoglycans (GAGs). We have shown previously that the GAG low molecular weight heparin (LMWH) binds to Aβ40 fibrils with a three-fold-symmetric (3Q) morphology with higher affinity than Aβ40 fibrils in alternative structures, Aβ42 fibrils, or amyloid fibrils formed from other sequences. Solid-state NMR (SSNMR) analysis of the GAG-3Q fibril complex revealed an interaction site at the corners of the 3Q fibril structure, but the origin of the binding specificity remained obscure...
July 8, 2017: Journal of Molecular Biology
Maryam Khoshouei, Radostin Danev, Juergen M Plitzko, Wolfgang Baumeister
Sixty years ago the first protein structure was determined by John Kendrew and his colleagues, that of myoglobin; haemoglobin followed shortly thereafter. For quite some time it seemed that only X-ray crystallography would be capable of determining the structure of proteins to high resolution. In recent years, cryo- electron microscopy has emerged as a viable alternative and indeed in many cases the preferred approach. It is capable of studying proteins which span a size range from several megadaltons to proteins as small as myoglobin and haemoglobin...
July 8, 2017: Journal of Molecular Biology
Christopher L Schwebach, Richa Agrawal, Steffen Lindert, Elena Kudryashova, Dmitri S Kudryashov
The actin cytoskeleton is a complex network controlled by a vast array of intricately regulated actin binding proteins. Human plastins (PLS1, 2, and 3) are evolutionary conserved proteins that non-covalently crosslink actin filaments into tight bundles. Through stabilization of such bundles, plastins contribute, in an isoform-specific manner, to the formation of kidney and intestinal microvilli, inner ear stereocilia, immune synapses, endocytic patches, adhesion contacts, and invadosomes of immune and cancer cells...
July 7, 2017: Journal of Molecular Biology
Tiffany F Chen, Stephen L Sazinsky, Damian Houde, David J DiLillo, Julie Bird, Kevin K Li, George T Cheng, Huawei Qiu, John R Engen, Jeffrey V Ravetch, K Dane Wittrup
The binding of human IgG1 to human Fc gamma receptors (hFcγR) is highly sensitive to the presence of a single N-linked glycosylation site at asparagine 297 of the Fc, with deglycosylation resulting in a complete loss of hFcγR binding. Previously, we demonstrated that aglycosylated human IgG1 Fc variants can engage the human FcγRII class of the low-affinity hFcγRs, demonstrating that N-linked glycosylation of the Fc is not a strict requirement for hFcγR engagement. In the present study, we demonstrate that aglycosylated IgG variants can be engineered to productively engage with FcγRIIIA, as well as the human Fc gamma RII subset...
July 7, 2017: Journal of Molecular Biology
R Stegeman, V M Weake
Genome-wide studies of aging have identified subsets of genes that show age-related changes in expression. Although the types of genes that are age regulated vary among different tissues and organisms, some patterns emerge from these large data sets. First, aging is associated with a broad induction of stress response pathways, although the specific genes and pathways involved differ depending on cell type and species. In contrast, a wide variety of functional classes of genes are downregulated with age, often including tissue-specific genes...
July 3, 2017: Journal of Molecular Biology
Ariel Waisman, Camila Vazquez Echegaray, Claudia Solari, María Soledad Cosentino, Iain Martyn, Alessia Deglincerti, Mohammad Zeeshan Ozair, Albert Ruzo Matias, Lino Barañao, Santiago Miriuka, Ali Brivanlou, Alejandra Guberman
The cell cycle has gained attention as a key determinant for cell fate decisions, but the contribution of DNA replication and mitosis in stem cell differentiation has not been extensively studied. To understand if these processes act as 'windows of opportunity' for changes in cell identity, we established synchronized cultures of mouse embryonic stem cells (mESC) as they exit the ground state of pluripotency. We show that initial transcriptional changes in this transition do not require passage through mitosis, and that conversion to primed pluripotency is linked to lineage priming in the G1 phase...
July 3, 2017: Journal of Molecular Biology
Yang Liu, Olga A Nikolaitchik, Sheikh Abdul Rahman, Jianbo Chen, Vinay K Pathak, Wei-Shau Hu
Genome packaging is an essential step to generate infectious HIV-1 virions and is mediated by interactions between the viral protein Gag and cis-acting elements in the full-length RNA. The sequence necessary and sufficient to allow RNA genome packaging into an HIV-1 particle has not been defined. Here, we used two distinct reporter systems to determine the HIV-1 sequence required for heterologous, non-viral RNAs to be packaged into viral particles. Although the 5' untranslated region (UTR) of the HIV-1 RNA is known to be important for RNA packaging, we found that its ability to mediate packaging relies heavily on the context of the downstream sequences...
June 30, 2017: Journal of Molecular Biology
Charis Georgiou, Iain McNae, Martin Wear, Harris Ioannidis, Julien Michel, Malcolm Walkinshaw
Fragment Based Drug Discovery (FBDD) is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance (SPR) experiments and molecular dynamics (MD) simulations, for the characterisation of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family...
June 30, 2017: Journal of Molecular Biology
Daniel Wefers, Janaina J V Cavalcante, Rachel R Schendel, Jaigeeth Deveryshetty, Kui Wang, Zdzislaw Wawrzak, Roderick I Mackie, Nicole M Koropatkin, Isaac Cann
Arabinoxylans are constituents of the human diet. Although not utilizable by the human host, they can be fermented by colonic bacteria. The arabinoxylan backbone is decorated with arabinose side-chains that may be substituted with ferulic acid, thus limiting depolymerization to fermentable sugars. We investigated the polypeptides encoded by two genes upregulated during growth of the colonic bacterium Bacteroides intestinalis on wheat arabinoxylan. The recombinant proteins, designated BiFae1A and BiFae1B, were functionally assigned esterase activities...
June 29, 2017: Journal of Molecular Biology
L Ponoop Prasad Patro, Abhishek Kumar, Narendar Kolimi, Thenmalarchelvi Rathinavelan
The inherent conformational flexibility of nucleic acids facilitate the formation of a range of conformations such as duplex, triplex, quadruplex etc. that play crucial roles in biological processes. Elucidation about the influence of non-canonical base pair mismatches on DNA/RNA structures at different sequence contexts to understand mismatch repair and misregulation of alternative splicing mechanisms as well as the sequence dependent effect of RNA-DNA hybrid in relevance to antisense strategy demand their three-dimensional structural information...
June 23, 2017: Journal of Molecular Biology
Nicholas C Wu, Ian A Wilson
Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin (HA) glycoprotein, which is the major antigen on the surface of the virus. The HA is composed of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively...
June 23, 2017: Journal of Molecular Biology
Hongchun Li, Nanaocha Sharma, Ignacio J General, Gideon Schreiber, Ivet Bahar
How structural dynamics affects cytokine signaling is under debate. Here, we investigated the dynamics of the type I interferon (IFN) receptor, IFNAR1, and its effect on signaling upon binding IFN and IFNAR2 using a combination of structure-based mechanistic studies, in situ binding and gene induction assays. Our study reveals that IFNAR1 flexibility modulates ligand-binding affinity, which, in turn, regulates biological signaling. We identified the hinge sites and key interactions implicated in IFNAR1 inter-subdomain (SD1-SD4) movements...
June 22, 2017: Journal of Molecular Biology
Sherine E Thomas, Vitor Mendes, So Yeon Kim, Sony Malhotra, Bernardo Ochoa-Montaño, Michal Blaszczyk, Tom L Blundell
Interest in applications of protein crystallography to medicine was evident as the first high-resolution structures emerged in the 50s and 60s. In Cambridge Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to haemoglobin, while in Oxford the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimisation of interactions of hits using the structure of the target protein...
June 22, 2017: Journal of Molecular Biology
Maria Birkou, Christos T Chasapis, Konstantinos D Marousis, Ariadni K Loutsidou, Detlef Bentrop, Moreno Lelli, Torsten Herrmann, Jonathon M Carthy, Vasso Episkopou, Georgios A Spyroulias
Arkadia (Rnf111) is an E3 ubiquitin ligase that plays a central role in the amplification of transforming growth factor beta (TGF-β) signaling responses by targeting for degradation the negative regulators of the pathway, Smad6 and Smad7, and the nuclear co-repressors Ski and Skil (SnoN). Arkadia's function in vivo depends on the really interesting new gene (RING)-H2 interaction with the E2 enzyme UbcH5b in order to ligate ubiquitin chains on its substrates. A conserved tryptophan (W972) in the C-terminal α-helix is widely accepted as essential for E2 recruitment and interaction and thus also for E3 enzymatic activity...
June 22, 2017: Journal of Molecular Biology
Ben A Bailey-Elkin, Robert C M Knaap, Marjolein Kikkert, Brian L Mark
Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication...
June 16, 2017: Journal of Molecular Biology
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