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Journal of Molecular Biology

Run-Zhi Lai, Khoosheh K Gosink, John S Parkinson
Residues E402 and R404 of the E. coli serine chemoreceptor, Tsr, appear to form a salt bridge that spans the interfaces between neighboring dimers in the Tsr trimer of dimers, a key structural component of receptor core signaling complexes. To assess their functional roles we constructed full sets of single amino acid replacement mutants at E402 and R404 and characterized their signaling behaviors with a suite of in vivo assays. Our results indicate that the E402 and R404 residues of Tsr play their most critical signaling roles at their inner locations near the trimer axis where they likely participate in stabilizing trimer-of-dimer packing and the kinase-ON state of core signaling complexes...
February 16, 2017: Journal of Molecular Biology
Christina Ambrosi, Massimiliano Manzo, Tuncay Baubec
DNA methylation is one of the most extensively studied epigenetic marks. It is involved in transcriptional gene silencing, it plays important roles during mammalian development and its perturbation is often associated with human diseases. In mammalian genomes, DNA methylation is a prevalent modification that decorates the majority of cytosines. It is found at the promoters and enhancers of inactive genes, at repetitive elements and within transcribed gene bodies. Its presence at promoters is dynamically linked to gene activity, suggesting that it could directly influence gene expression patterns and cellular identity...
February 15, 2017: Journal of Molecular Biology
Anthony J Rampello, Steven E Glynn
The i-AAA protease is a component of the mitochondrial quality control machinery that regulates respiration, mitochondrial dynamics, and protein import. The protease is required to select specific substrates for degradation from among the diverse complement of proteins present in mitochondria, yet the rules that govern this selection are unclear. Here, we reconstruct the yeast i-AAA protease, Yme1p, to examine the in vitro degradation of two intermembrane space chaperone subunits, Tim9 and Tim10. Yme1p degrades Tim10 more rapidly than Tim9 despite high sequence and structural similarity, and loss of Tim10 is accelerated by disruption of conserved disulfide bonds within the substrate...
February 15, 2017: Journal of Molecular Biology
Anne Galinier, Josef Deutscher
The phosphoenolpyruvate:sugar phosphotransferase system (PTS) is a carbohydrate transport and phosphorylation system present in bacteria of all different phyla and in archaea. It is usually composed of three proteins or protein complexes, enzyme I, HPr and enzyme II, which are phosphorylated at histidine or cysteine residues. However, in many bacteria, HPr can also be phosphorylated at a serine residue. The PTS functions not only as carbohydrate transporter, but also regulates numerous cellular processes by either phosphorylating its target proteins or by interacting with them in a phosphorylation-dependent manner...
February 12, 2017: Journal of Molecular Biology
Thomas Mager, Phillip G Wood, Ernst Bamberg
Ca(2+) concentration jumps for the activation of Ca(2+) dependent ion channels or transporters can be obtained either by fast solution exchange or the use of caged Ca(2+). Here we report on an alternate optogenetic method for activation of Ca(2+) and voltage dependent large conductance (BK) potassium channels. This was achieved through the use of the light-gated Ca(2+) permeable Channelrhodopsin 2 variant, CatCh, with enhanced Ca(2+) permeability, which produces locally [Ca(2+)] in the μM range on the inner side of the membrane, without significant [Ca(2+)] increase in the cytosol...
February 10, 2017: Journal of Molecular Biology
Koyel Ghosal, Jennifer M Colby, Debasis Das, Stephen T Joy, Paramjit S Arora, Bryan A Krantz
Anthrax toxin is an intracellularly acting toxin where sufficient detail is known about the structure of its channel, allowing for molecular investigations of translocation. The toxin is comprised of three proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF). The toxin's translocon, PA, translocates the large enzymes, LF and EF, across the endosomal membrane into the host cell's cytosol. Polypeptide clamps located throughout the PA channel catalyze the translocation of LF and EF. Here we show that the central peptide clamp, the ϕ clamp, is a dynamic site that governs the overall peptide translocation pathway...
February 10, 2017: Journal of Molecular Biology
Jessica Winger, Gregory D Bowman
Chromatin remodelers are ATP-dependent enzymes that are critical for reorganizing and repositioning nucleosomes in concert with many basic cellular processes. For the Chromodomain Helicase DNA Binding Protein 1 (Chd1) remodeler, nucleosome sliding has been shown to depend on DNA flanking the nucleosome, transcription factor binding at the nucleosome edge, and the presence of the histone H2A/H2B dimer on the entry side. Here we report that Chd1 is also sensitive to the sequence of DNA within the nucleosome, and slides nucleosomes made with the 601 Widom positioning sequence asymmetrically...
February 8, 2017: Journal of Molecular Biology
Jeffrey Seow, Rodrigo A V Morales, Christopher A MacRaild, Bankala Krishnarjuna, Sheena McGowan, Tamir Dingjan, Garima Jaipuria, Romain Rouet, Karyn L Wilde, Hanudatta S Atreya, Jack S Richards, Robin F Anders, Daniel Christ, Nyssa Drinkwater, Raymond S Norton
Merozoite surface protein 2 (MSP2) is an intrinsically disordered antigen that is abundant on the surface of the malaria parasite Plasmodium falciparum. The two allelic families of MSP2, 3D7 and FC27, differ in their central variable regions, which are flanked by highly conserved C-terminal and N-terminal regions. In a vaccine trial, full-length 3D7 MSP2 induced a strain-specific protective immune response despite the detectable presence of conserved region antibodies. This work focuses on the conserved C-terminal region of MSP2, which includes the only disulfide bond in the protein and encompasses key epitopes recognised by the mouse monoclonal antibodies (mAb) 4D11 and 9H4...
February 8, 2017: Journal of Molecular Biology
Maradumane L Mohan, Sathyamangla V Naga Prasad
Traditionally, an enzyme is a protein that mediates biochemical action by binding to the substrate and by catalyzing the reaction that translates external cues into biological responses. Sequential dissemination of information from one enzyme to another facilitates signal transduction in biological systems providing for feed-forward and feed-back mechanisms. Given this viewpoint, an enzyme without its catalytic activity is generally considered to be an inert organizational protein without catalytic function and has classically been termed as pseudo-enzymes...
February 6, 2017: Journal of Molecular Biology
Wan Seok Song, So Yeon Cho, Ho Jeong Hong, Sun Cheol Park, Sung-Il Yoon
FliD is a self-oligomerizing structural protein that caps the growing end of the bacterial flagellar filament. FliD also plays a key role in the flagellar system by continuously adding a new flagellin protein to the tip of the filament. To structurally characterize FliD oligomerization and to provide a FliD-mediated flagellin polymerization mechanism, we have determined the crystal structures of FliD proteins from Escherichia coli and Salmonella enterica serovar Typhimurium (ecFliD and stFliD, respectively)...
February 6, 2017: Journal of Molecular Biology
Fabio Alexis Lefebvre, Louis Philip Benoit Bouvrette, Julie Bergalet, Eric Lécuyer
In higher eukaryotes, maternally provided gene products drive the initial stages of embryogenesis until the zygotic transcriptional program takes over, a developmental process called the midblastula transition (MBT). In addition to zygotic genome activation, the MBT involves alterations in cell-cycle length and the implementation of DNA damage/replication checkpoints that serve to monitor genome integrity. Previous work has shown that mutations affecting histone mRNA metabolism or DNA replication checkpoint factors severely impact developmental progression through the MBT, prompting us to characterize and contrast the transcriptomic impact of these genetic perturbations...
February 3, 2017: Journal of Molecular Biology
Christine Wachnowsky, Nathaniel A Wesley, Insiya Fidai, J A Cowan
Iron-sulfur (Fe/S) cluster-containing proteins constitute one of the largest protein classes, with varied functions that include electron transport, regulation of gene expression, substrate binding and activation, and radical generation. Consequently, the biosynthetic machinery for Fe/S clusters is evolutionarily conserved, and mutations in a variety of putative intermediate Fe/S cluster scaffold proteins can cause disease states, including multiple mitochondrial dysfunctions syndrome (MMDS), sideroblastic anemia and mitochondrial encephalomyopathy...
February 1, 2017: Journal of Molecular Biology
John A Hammond, Rajan Lamichhane, David P Millar, James R Williamson
Nuclear export of partially spliced or unspliced HIV-1 RNA transcripts requires binding of the viral protein regulator of expression of virion (Rev) to the Rev response element (RRE) and subsequent oligomerization in a cooperative manner. Cellular DEAD-box helicase DEAD-box protein 1 (DDX1) plays a role in HIV replication, interacting with and affecting Rev-containing HIV transcripts in vivo, interacting directly with the RRE and Rev in vitro, and promoting Rev oligomerization in vitro. Binding of DDX1 results in enhancement of Rev oligomerization on the RRE that is correlated with an RNA structural change within the RRE that persists even after dissociation of DDX1...
January 31, 2017: Journal of Molecular Biology
Silvana Jananji, Cristina Risi, Indeewari K S Lindamulage, Louis-Philippe Picard, Robert Van Sciver, Guillaume Laflamme, Abe Albaghjati, Gilles R X Hickson, Benjamin H Kwok, Vitold E Galkin
Cytokinesis of animal cells requires the assembly of a contractile ring, which promotes daughter cell splitting. Anillin is a conserved scaffold protein involved in organizing the structural components of the contractile ring including filamentous actin (F-actin), myosin, and septins and in forming the subsequent midbody ring. Like other metazoan homologs, Drosophila anillin contains a conserved domain that can bind and bundle F-actin, but the importance and molecular details of its interaction with F-actin remain unclear...
January 29, 2017: Journal of Molecular Biology
Roumita Moulick, Jayant B Udgaonkar
To identify and structurally characterize the precursor conformation of the prion protein (PrP), from which misfolding and aggregation directly commence, has been a long-standing goal. Misfolding converts the α-helical, non-pathogenic functional form of PrP to pathogenic, β-structured oligomeric and amyloidogenic forms, which are the cause of prion diseases. Susceptibility to sporadic prion disease correlates well with the propensity of PrP to misfold to cytotoxic, proteinase K resistant oligomeric conformations at low pH...
January 29, 2017: Journal of Molecular Biology
Alexander L Chernorudskiy, Ester Zito
Calcium signaling plays an important role in cell survival by influencing mitochondria-related processes such as energy production and apoptosis. The endoplasmic reticulum (ER) is the main storage compartment for cell calcium (Ca(2+); ~60-500μM), and the Ca(2+) released by the ER has a prompt effect on the homeostasis of the juxtaposed mitochondria. Recent findings have highlighted a close connection between ER redox and Ca(2+) signaling that is mediated by Ca(2+)-handling proteins. This paper describes the redox-regulated mediators and mechanisms that orchestrate Ca(2+) signals from the ER to mitochondria...
January 28, 2017: Journal of Molecular Biology
Miao Li, Qiang Dong, Bing Zhu
Serine 31 of histone H3.3 is phosphorylated during mitosis in mammalian cells and has been shown to influence chromosome segregation. We established a screening system to identify candidate kinase(s) phosphorylating H3.3S31 by using siRNA library targeting 720 human kinases, and we confirmed the results with an independent kinase inhibitor screen. Aurora kinase B was the best candidate hit in both screens. Moreover, the kinase activity of Aurora B on H3.3S31 was biochemically confirmed with nucleosomal substrates in vitro...
January 27, 2017: Journal of Molecular Biology
Maxime Bodak, Daniel Cirera-Salinas, Janina Luitz, Constance Ciaudo
Complex gene regulation systems ensure maintenance of cellular identity during early development in mammals. Eukaryotic small RNAs have emerged as critical players in RNA interference (RNAi) by mediating gene silencing during embryonic stem cell self-renewal. Most of the proteins involved in the biogenesis of small RNAs are essential for proliferation and differentiation into the three germ layers of mouse embryonic stem cells (mESCs). In the last decade, new functions for some RNAi proteins, independent of their roles in RNAi pathways, have been demonstrated in different biological systems...
January 21, 2017: Journal of Molecular Biology
Debasis Das, Bryan A Krantz
In order for many proteins to move across hydrophobic membrane bilayers, they must be unfolded and translocated by a membrane-embedded channel. These translocase channels interact with the substrate proteins they translocate via hydrophobic pore loops and cleft structures, called clamps. The molecular basis for how clamps facilitate unfolding and translocation is poorly understood. Anthrax toxin is comprised of three proteins, a translocase channel forming subunit, called protective antigen (PA), and two substrate proteins, called lethal factor (LF) and edema factor...
January 20, 2017: Journal of Molecular Biology
Yulia Vasianovich, Raymund J Wellinger
Telomerase reverse transcriptase elongates telomeres to overcome their natural attrition and allow unlimited cellular proliferation, a characteristic shared by stem cells as well as the majority of malignant cancerous cells. The telomerase holoenzyme comprises a core RNA molecule, a catalytic protein subunit and other accessory proteins. Malfunction of certain telomerase components can cause serious genetic disorders including dyskeratosis congenita and aplastic anemia. A hierarchy of tightly regulated steps constitute the process of telomerase biogenesis, which if interrupted or misregulated, can impede production of a functional enzyme and severely affect telomere maintenance...
January 20, 2017: Journal of Molecular Biology
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