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Journal of Molecular Biology

Caizhen Hu, Vikas Malik, Yiming Kenny Chang, Veeramohan Veerapandian, Yogesh Srivastava, Yong-Heng Huang, Linlin Hou, Vlad Cojocaru, Gary D Stormo, Ralf Jauch
Sox2 and Pax6 co-regulate genes in neural lineages and the lens by forming a ternary complex likely facilitated allosterically through DNA. We used the quantitative and scalable Cooperativity-by-sequencing (Coop-seq) approach to interrogate Sox2/Pax6 dimerization on a DNA library where five positions of the Pax6 half-site were randomized yielding 1024 cooperativity factors. Consensus positions normally required for the high-affinity DNA binding by Pax6 need to be mutated for effective dimerization with Sox2...
October 16, 2017: Journal of Molecular Biology
Erik D Holmstrom, Daniel Nettels, Benjamin Schuler
Many of the unanswered questions associated with hepatitis C virus assembly are related to the core protein (HCVcp), which forms an oligomeric nucleocapsid encompassing the viral genome. The structural properties of HCVcp have been difficult to quantify, at least in part because it is an intrinsically disordered protein (IDP). We have used single-molecule FRET techniques to study the conformational dimensions and dynamics of the HCVcp nucleocapsid domain (HCVncd) at various stages during the RNA-induced formation of nucleocapsid-like particles...
October 15, 2017: Journal of Molecular Biology
Joakim Karlsson, Thomas Kroneis, Emma Jonasson, Erik Larsson, Anders Ståhlberg
The highly fine-tuned dynamics of cell cycle gene expression have been intensely studied for several decades. However, some previous observations may be difficult to fully decouple from artifacts induced by traditional cell synchronization procedures. In addition, bulk cell measurements may have disguised intricate details. Here, we address this by sorting and transcriptomic sequencing of single cells progressing through the cell cycle without prior synchronization. Genes and pathways with known cell cycle roles are confirmed, associated regulatory sequence motifs are determined and we also establish ties between other biological processes and the unsynchronized cell cycle...
October 15, 2017: Journal of Molecular Biology
Deepak Sharma, Andrea A Putnam, Eckhard Jankowsky
DDX3X is a conserved DEAD-box RNA helicase involved in translation initiation and other processes of RNA metabolism. Mutations in human DDX3X and deregulation of its expression are linked to tumorigenesis and intellectual disability. The protein is also targeted by diverse viruses. Previous studies demonstrated helicase and NTPase activities for DDX3X, but important biochemical features of the enzyme remain unclear. Here, we systematically characterize enzymatic activities of human DDX3X and compare these to its closely related S...
October 13, 2017: Journal of Molecular Biology
Jean-Claude Farré, Krypton Carolino, Oleh V Stasyk, Olena G Stasyk, Zlatan Hodzic, Gaurav Agrawal, Andreas Till, Marco Proietto, James Cregg, Andriy A Sibirny, Suresh Subramani
Peroxisomal membrane proteins (PMPs) traffic to peroxisomes by two mechanisms: direct insertion from the cytosol into the peroxisomal membrane and indirect trafficking to peroxisomes via the endoplasmic reticulum (ER). In mammals and yeast, several PMPs traffic via the ER in a Pex3- and Pex19-dependent manner. In Komagataella phaffii (formerly called Pichia pastoris) specifically, the indirect traffic of Pex2, but not of Pex11 or Pex17, depends on Pex3, but all PMPs tested for indirect trafficking require Pex19...
October 13, 2017: Journal of Molecular Biology
Kevin Macé, Fanny Demay, Charlotte Guyomar, Sylvie Georgeault, Emmanuel Giudice, Renan Goude, Annie Trautwetter, Gwennola Ermel, Carlos Blanco, Reynald Gillet
In bacteria, trans-translation is the main quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and plays a critical role in the viability and virulence of many pathogens. We developed a reliable in vivo double-fluorescence reporter system for the simultaneous quantification of both trans-translation and the associated proteolysis activities in bacteria. The assay was validated using mutant bacteria lacking tmRNA, SmpB, and the ClpP protease...
October 12, 2017: Journal of Molecular Biology
Yiming Wang, David C Latshaw, Carol K Hall
Although some naturally-occurring polyphenols have been found to inhibit amyloid β fibril formation and reduce neuron cell toxicity in vitro, their exact inhibitory mechanism is unknown. In this work, discontinuous molecular dynamics (DMD) combined with the PRIME20 force field and a newly-built inhibitor model are performed to examine the effect of vanillin, resveratrol, curcumin and epigallocatechin-3-gallate (EGCG) on the aggregation of Aβ(17-36) peptides. Four sets of peptide/inhibitor simulations are performed in which inhibitors: (1) bind to Aβ(17-36) monomer; (2) interfere with Aβ(17-36) oligomerization; (3) disrupt a pre-formed Aβ(17-36) protofilament; (4) prevent the growth of Aβ(17-36) protofilament...
October 12, 2017: Journal of Molecular Biology
Michael G Kattah, Barbara A Malynn, Averil Ma
Ubiquitin and ubiquitin-modifying enzymes play critical roles in a wide variety of intracellular signaling pathways. Inflammatory signaling cascades downstream of TNF, TLR agonists, antigen receptor cross-linking, and cytokine receptors, all rely on ubiquitination events to direct subsequent immune responses. In the past several years, inflammasome activation and subsequent signal transduction have emerged as an excellent example of how ubiquitin signals control inflammatory responses. Inflammasomes are multiprotein signaling complexes that ultimately lead to caspase activation and release of the interleukin-1 (IL-1) family members, IL-1β and IL-18...
October 12, 2017: Journal of Molecular Biology
Simon Hartmann, Airat Gubaev, Dagmar Klostermeier
Topoisomerases catalyze the relaxation, supercoiling, catenation, and decatenation of DNA. Gyrase is a bacterial topoisomerase that introduces negative supercoils into DNA in an ATP-dependent reaction. The enzyme consists of two GyrB subunits, containing the ATPase domains, and two GyrA subunits. Nucleotide binding to GyrB causes closing of the N-gate in gyrase, which orients bound DNA for supercoiling. N-gate re-opening after ATP hydrolysis, at the end of the supercoiling reaction, resets the enzyme for subsequent catalytic cycles...
October 11, 2017: Journal of Molecular Biology
Mohanalaxmi Indramohan, Christian Stehlik, Andrea Dorfleutner
Sensing and responding to pathogens and tissue damage is a core mechanism of innate immune host defense and inflammasomes represent a central cytosolic pattern recognition receptor (PRR) pathway leading to the generation of the pro-inflammatory cytokines IL-1β and IL-18 and pyroptotic cell death that causes the subsequent release of danger signals to propagate and perpetuate inflammatory responses. While inflammasome activation is essential for host defense, deregulated inflammasome responses and excessive release of inflammatory cytokines and danger signals are linked to an increasing spectrum of inflammatory diseases...
October 9, 2017: Journal of Molecular Biology
Galit Yom-Tov, Reut Barak, Omri Matalon, Mira Barda-Saad, Julia Guez-Haddad, Yarden Opatowsky
Robo receptors play pivotal roles in axonal guidance as well as in neurogenesis, angiogenesis, cell migration, and cancer progression and invasiveness. They are considered to be attractive drug targets for the treatment of cancer, ocular neovascular disorders, chronic kidney diseases, and more. Despite their great importance, the mechanisms by which Robo receptors switch from their "off" to "on" states remain obscure. One possibility involves a monomer-to-dimer or dimer-to-monomer transition that facilitates the recruitment and activation of enzymatic effectors to instigate intracellular signaling...
October 7, 2017: Journal of Molecular Biology
Ashley J Russo, Bharat Behl, Ishita Banerjee, Vijay A K Rathinam
Inflammasomes are cytosolic multi-molecular complexes that sense intracellular microbial danger signals and metabolic perturbations. Inflammasome activation leads to the activation of caspase-1 and the release of pro-inflammatory cytokines IL-1β and IL-18 accompanied by cell death. An inflammasome-based surveillance machinery for Gram-negative bacterial infections has been recently discovered. This noncanonical inflammasome relies on sensing the cytosolic presence of lipopolysaccharide (LPS) of Gram-negative bacteria via inflammatory caspases such as caspase-4, -5, and -11...
October 7, 2017: Journal of Molecular Biology
Swati Jain, Tamar Schlick
Coarse-grained models represent attractive approaches to analyze and simulate RNA molecules, for example for structure prediction and design, as they simplify the RNA structure to reduce the conformational search space. Our structure prediction protocol RAGTOP (RNA-As-Graphs Topology Prediction) represents RNA structures as tree graphs, and samples graph topologies to produce candidate graphs. However, for a more detailed study and analysis, construction of atomic from coarse-grained models is required. Here we present our graph-based fragment assembly algorithm (F-RAG) to convert candidate 3D tree graph models, produced by RAGTOP into atomic structures...
October 5, 2017: Journal of Molecular Biology
Stefanie A H de Poot, Geng Tian, Daniel Finley
Three deubiquitinating enzymes-Rpn11, Usp14, and Uch37-are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel's entry port, where they can impede further translocation...
October 5, 2017: Journal of Molecular Biology
Charles Evavold, Jonathan C Kagan
An immune response consists of a finely orchestrated interplay between initial recognition of potential microbial threats by the innate immune system and subsequent licensed adaptive immune neutralization. The initial recognition integrates environmental cues derived from pathogen associated molecular patterns (PAMPs) and cell intrinsic damage associated molecular patterns (DAMPs) to contextualize the insult and inform a tailored adaptive response via T and B lymphocytes. While there is much data to support the role of transcriptional responses downstream of pattern recognition receptors (PRRs) in informing the adaptive immune response, markedly less attention has been paid to the role of post-translational responses to PAMP and DAMP recognition by the innate immune system, and how this may influence adaptive immunity...
October 5, 2017: Journal of Molecular Biology
Reinke T Müller, Timothy Travers, Hi-Jea Cha, Joshua L Phillips, S Gnanakaran, Klaas M Pos
The functionally important switch-loop of the trimeric multidrug transporter AcrB separates the access and deep drug binding pockets in every protomer. This loop, comprising 11 amino acid residues, has been shown to be crucial for substrate transport, as drugs have to travel past the loop to reach the deep binding pocket and from there are transported outside the cell via the connected AcrA and TolC channels. It contains four symmetrically arranged glycine residues suggesting that flexibility is a key feature for pump activity...
October 5, 2017: Journal of Molecular Biology
Joshua W Francis, Devrishi Goswami, Scott J Novick, Bruce D Pascal, Emily R Weikum, Eric A Ortlund, Patrick R Griffin, Richard A Kahn
Microtubules are highly dynamic tubulin polymers that are required for a variety of cellular functions. Despite the importance of a cellular population of tubulin dimers, we have incomplete information about the mechanisms involved in the biogenesis of αβ-tubulin heterodimers. In addition to prefoldin and the TCP-1 Ring Complex, five tubulin-specific chaperones, termed cofactors A-E (TBCA-E), and GTP are required for the folding of α- and β-tubulin subunits and assembly into heterodimers. We recently described the purification of a novel trimer, TBCD•ARL2•β-tubulin...
September 29, 2017: Journal of Molecular Biology
Gabriel Talaia, Christos Gournas, Elie Saliba, Cláudia Barata-Antunes, Margarida Casal, Bruno André, George Diallinas, Sandra Paiva
Eukaryotic α-arrestins connect environmental or stress signaling pathways to the endocytosis of plasma membrane transporters or receptors. The Saccharomyces cerevisiae lactate transporter Jen1p has been used as a model cargo for elucidating the mechanisms underlying endocytic turnover in response to carbon sources. Here, we discover a novel pathway of Jen1p endocytosis mediated by the α-arrestin Bul1p in response to the presence of cycloheximide or rapamycin, or prolonged growth in lactate. While cycloheximide or rapamycin modify cells pleiotropically, the major effect of prolonged growth in lactate was shown to be external pH alkalinization...
September 28, 2017: Journal of Molecular Biology
Wenyu Wen, Mingjie Zhang
Asymmetric local concentration of protein complexes on distinct membrane regions is a fundamental property in numerous biological processes and is a hallmark of cell polarity. Evolutionarily conserved core polarity proteins form specific and dynamic networks to regulate the establishment and maintenance of cell polarity, as well as distinct polarity-driven cellular events. This review focuses on the molecular and structural basis governing regulated formation of several sets of core cell polarity regulatory complexes, as well as their functions in epithelial cell polarization and asymmetric cell division...
September 27, 2017: Journal of Molecular Biology
R Stefan Isaac, Serena Sanulli, Ryan Tibble, Michael Hornsby, Matthew Ravalin, Charles S Craik, John D Gross, Geeta J Narlikar
Heterochromatin protein 1 (HP1) family proteins are conserved chromatin binding proteins involved in gene silencing, chromosome packaging, and chromosome segregation. These proteins recognize histone H3 lysine 9 methylated tails via their chromodomain (CD) and recruit additional ligand proteins with diverse activities through their dimerization domain, the chromoshadow domain (CSD). Species that have HP1 proteins possess multiple paralogs that perform non-overlapping roles in vivo. How different HP1 proteins, which are highly conserved, perform different functions is not well understood...
September 20, 2017: Journal of Molecular Biology
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