31,216 results match your criteria Journal of Molecular Biology[Journal]


An Expanded Conformation of an Antibody Fab Region by X-Ray Scattering, Molecular Dynamics and smFRET Identifies an Aggregation Mechanism.

J Mol Biol 2019 Feb 15. Epub 2019 Feb 15.

Department of Biochemical Engineering, University College London, Gordon Street, London, WC1E 7JE, UK. Electronic address:

Protein aggregation is the underlying cause of many diseases, and also limits the usefulness of many natural and engineered proteins in biotechnology. Better mechanistic understanding and characterization of aggregation-prone states, is needed to guide protein engineering, formulation, and drug-targeting strategies that prevent aggregation. While several final aggregated states - notably amyloids - have been characterized structurally, very little is known about the native structural conformers that initiate aggregation. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.009DOI Listing
February 2019

Relative Binding Affinity Prediction of Charge-Changing Sequence Mutations with FEP in Protein-Protein Interfaces.

J Mol Biol 2019 Feb 15. Epub 2019 Feb 15.

Department of Chemistry, Columbia University, 3000 Broadway, MC 3178, New York, NY 10027, USA.

Building on the substantial progress that has been made in using free energy perturbation (FEP) methods to predict the relative binding affinities of small molecule ligands to proteins, we have previously shown that results of similar quality can be obtained in predicting the effect of mutations on the binding affinity of protein-protein complexes. However, these results were restricted to mutations which did not change the net charge of the side chains due to known difficulties with modeling perturbations involving a change in charge in FEP. Various methods have been proposed to address this problem. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.003DOI Listing
February 2019

Xenogeneic Regulation of the Bacterial Transcription Machinery.

J Mol Biol 2019 Feb 15. Epub 2019 Feb 15.

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, SW7 2AZ, UK. Electronic address:

The parasitic life cycle of viruses involves the obligatory subversion of the host's macromolecular processes for efficient viral progeny production. Viruses that infect bacteria, bacteriophages (phages), are no exception and have evolved sophisticated ways to control essential biosynthetic machineries of their bacterial prey to benefit phage development. The xenogeneic regulation of bacterial cell function is a poorly understood area of bacteriology. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.008DOI Listing
February 2019

Visualization and Analysis of Epiproteome Dynamics.

J Mol Biol 2019 Feb 12. Epub 2019 Feb 12.

University of New South Wales (UNSW); Garvan Institute of Medical Research; CSIRO. Electronic address:

The epiproteome describes the set of all post-translational modifications (PTMs) made to the proteins comprising a cell or organism. The extent of the epiproteome is still largely unknown, however, advances in experimental techniques are beginning produce a deluge of data, tracking dynamic changes to the epiproteome in response to cellular stimuli. These data have potential to revolutionize our understanding of biology and disease. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.044DOI Listing
February 2019

Evolved Biofilm: Review on the Experimental Evolution Studies of Bacillus subtilis Pellicles.

J Mol Biol 2019 Feb 12. Epub 2019 Feb 12.

Bacterial Interactions and Evolution Group, Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Electronic address:

For several decades, laboratory evolution has served as a powerful method to manipulate microorganisms and to explore long-term dynamics in microbial populations. Next to canonical Escherichia coli planktonic cultures, experimental evolution has expanded into alternative cultivation methods and species, opening the doors to new research questions. Bacillus subtilis, the spore-forming and root-colonizing bacterium, can easily develop in the laboratory as a liquid-air interface colonizing pellicle biofilm. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.005DOI Listing
February 2019
1 Read
4.333 Impact Factor

The Molecular Mechanisms Underlying Hidden Phenotypic Variation among Metallo-β-Lactamases.

J Mol Biol 2019 Feb 12. Epub 2019 Feb 12.

Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. Electronic address:

Genetic variation among orthologous genes has been largely formed through neutral genetic drift while maintaining their functional role. Yet, because the evolution of gene occurs within each organismal host, their sequence changes are also associated with adaptation to specific environment. Thus, genetic variation can create critical phenotypic variation, particularly when genes are transferred to a new host by horizontal gene transfer (HGT). Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.041DOI Listing
February 2019

Yeast Two-Hybrid Analysis for Ubiquitin-Variant Inhibitors of Human Deubiquitinases.

J Mol Biol 2019 Feb 11. Epub 2019 Feb 11.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S3E1, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address:

We applied a Yeast-Two-Hybrid (Y2H) analysis to screen for ubiquitin variant (UbV) inhibitors of a human deubiquitinase (DUB), ubiquitin-specific protease 2 (USP2). The Y2H screen used USP2 as the bait, and a prey library consisting of UbVs randomized at four specific positions, which were known to interact with USP2 from phage display analysis. The screen yielded numerous UbVs that bound to USP2 both as a Y2H interaction in vivo and as purified proteins in vitro. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.007DOI Listing
February 2019

Implications of Microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

J Mol Biol 2019 Feb 11. Epub 2019 Feb 11.

Group of Stem Cells and Modeling of Neurodegeneration, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, Grønnegårdsvej 7, 1870C. Electronic address:

Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes correlated with ALS and FTD are implicated in the same molecular pathways. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193006
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http://dx.doi.org/10.1016/j.jmb.2019.02.004DOI Listing
February 2019
5 Reads

The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca/CaM.

J Mol Biol 2019 Feb 9. Epub 2019 Feb 9.

Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404, United States of America. Electronic address:

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine protein kinase that transmits calcium signals in various cellular processes. CaMKII is activated by calcium-bound calmodulin (Ca/CaM) through a direct binding mechanism involving a regulatory C-terminal α-helix in CaMKII. The Ca/CaM binding triggers transphosphorylation of critical threonine residues proximal to the CaM-binding site leading to the autoactivated state of CaMKII. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.001DOI Listing
February 2019
4.333 Impact Factor

Cryo-EM Structures Reveal Relocalization of MetAP in the Presence of Other Protein Biogenesis Factors at the Ribosomal Tunnel Exit.

J Mol Biol 2019 Feb 9. Epub 2019 Feb 9.

Structural Biology & Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata-700 032, India. Electronic address:

During protein biosynthesis in bacteria, one of the earliest events that a nascent polypeptide chain goes through is the co-translational enzymatic processing. The event includes two enzymatic pathways: deformylation of the N-terminal methionine by the enzyme peptide deformylase (PDF), followed by methionine excision catalyzed by methionine aminopeptidase (MetAP). During the enzymatic processing, the emerging nascent protein likely remains shielded by the ribosome-associated chaperone trigger factor (TF). Read More

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http://dx.doi.org/10.1016/j.jmb.2019.02.002DOI Listing
February 2019

RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43.

J Mol Biol 2019 Feb 8. Epub 2019 Feb 8.

UK Dementia Research Institute at King's College London, London, SE5 9RT, United Kingdom; The Wohl Institute at King's College London, London, SE5 9RT, United Kingdom; Department of Medicina Molecolare, University of Pavia, Pavia, 27100, Italy. Electronic address:

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD) are incurable motor neuron diseases associated with muscle weakness, paralysis and respiratory failure. Accumulation of TAR DNA-binding protein 43 (TDP-43) as toxic cytoplasmic inclusions is one of the hallmarks of these pathologies. TDP-43 is an RNA-binding protein responsible for regulating RNA transcription, splicing, transport and translation. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.028DOI Listing
February 2019
2 Reads

Force-Profile Analysis of the Cotranslational Folding of HemK and Filamin Domains: Comparison of Biochemical and Biophysical Folding Assays.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden; Science for Life Laboratory Stockholm University, Box 1031, SE-171 21 Solna, Sweden. Electronic address:

We have characterized the cotranslational folding of two small protein domains of different folds - the α-helical N-terminal domain of HemK and the β-rich FLN5 filamin domain - by measuring the force that the folding protein exerts on the nascent chain when located in different parts of the ribosome exit tunnel (Force-Profile Analysis - FPA), allowing us to compare FPA to three other techniques currently used to study cotranslational folding: real-time FRET, PET, and NMR. We find that FPA identifies the same cotranslational folding transitions as do the other methods, and that these techniques therefore reflect the same basic process of cotranslational folding in similar ways. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.043DOI Listing
February 2019

Regulation of Monoamine Oxidase B Gene Expression: Key Roles for Transcription Factors Sp1, Egr1 and CREB, and microRNAs miR-300 and miR-1224.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India. Electronic address:

Monoamine oxidase B (MAO-B), a flavoenzyme located in the outer mitochondrial membrane, is involved in the catabolism of monoamines. Altered levels of MAO-B are associated with cardiovascular/neuronal diseases. However, molecular mechanisms of MAO-B gene regulation are partially understood. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.042DOI Listing
February 2019

Multiple Mechanisms Are Involved in Repression of Filamentous Phage SW1 Transcription by the DNA-Binding Protein FpsR.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; State Key Laboratory of Ocean Engineering, School of Naval Architecture, Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China. Electronic address:

SW1 is the first filamentous phage isolated from a deep-sea environment. Nevertheless, the mechanism by which the SW1 genetic switch is controlled is largely unknown. In this study, the function of the phage-encoded FpsR protein was characterized by molecular biological and biochemical analyses. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.040DOI Listing
February 2019

Microglia in Alzheimer's Disease: Exploring how Genetics and Phenotype Influence Risk.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA. Electronic address:

Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease, the majority of risk loci discovered through genome-wide association-studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of Alzheimer's disease (AD) from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.045DOI Listing
February 2019
1 Read

Emerging Role of microRNAs in Dementia.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, (inStem), Bangalo, re-560065, India. Electronic address:

MicroRNAs are small non-coding RNAs regulating mRNA translation. They play a crucial role in regulating homeostasis in neurons, especially in regulating local and stimulation dependent protein synthesis. Since activity mediated protein synthesis in neurons is critical for memory and cognition, microRNAs have become key players in modulating these processes. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.046DOI Listing
February 2019

Reverse Engineering of a Thermosensing Regulator Switch.

J Mol Biol 2019 Jan 25. Epub 2019 Jan 25.

Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 531, Universidad Nacional de Rosario, Argentine National Research Council (CONICET), Rosario, Argentina. Electronic address:

To address the mechanism of thermosensing and its implications for molecular engineering, we previously deconstructed the functional components of the bacterial thermosensor DesK, a histidine kinase with a five-span transmembrane domain that detects temperature changes. The system was first simplified by building a sensor that consists of a single chimerical transmembrane segment that retained full sensing capacity. Genetic and biophysical analysis of this minimal sensor enabled the identification of three modular components named determinants of thermodetection (DOTs). Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.025DOI Listing
January 2019

Virtual Reality: Beyond Visualisation.

J Mol Biol 2019 Feb 7. Epub 2019 Feb 7.

Decision and Bayesian Computation, CNRS UMR 3571, Institut Pasteur, Paris, France; Center for Biostatistics, Bioinformatics and Integrative Biology - C3BI, USR 3756 IP CNRS, Paris, France. Electronic address:

Virtual reality (VR) has recently become an affordable technology. A wide range of options are available to access this unique visualisation medium, from simple cardboard inserts for smartphones to truly advanced headsets tracked by external sensors. While it is now possible for any research team to gain access to VR, we can still question what it brings to scientific research. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.033DOI Listing
February 2019
1 Read

Characterization of Mitochondrial YME1L Protease Oxidative Stress-Induced Conformational State.

J Mol Biol 2019 Feb 5. Epub 2019 Feb 5.

Department of Chemistry, Middle Tennessee State University, 1301 East Main Street, Murfreesboro, TN 37132, USA. Electronic address:

Oxidative stress is a common challenge to mitochondrial function where reactive oxygen species are capable of significant organelle damage. The generation of mitochondrial reactive oxygen species occurs in the inner membrane and matrix compartments as a consequence of subunit function in the electron transport chain and citric acid cycle, respectively. Maintenance of mitochondrial proteostasis and stress response is facilitated by compartmentalized proteases that couple the energy of ATP hydrolysis to unfolding and the regulated removal of damaged, misfolded, or aggregated proteins. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.039DOI Listing
February 2019

Solution Conformation of Bovine Leukemia Virus Gag Suggests an Elongated Structure.

J Mol Biol 2019 Feb 4. Epub 2019 Feb 4.

Department of Chemistry and Biochemistry, Center for RNA Biology, and Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA.

Bovine leukemia virus (BLV) is a deltaretrovirus that infects domestic cattle. The structural protein Gag, found in all retroviruses, is a polyprotein comprising three major functional domains: matrix (MA), capsid (CA), and nucleocapsid (NC). Previous studies have shown that both mature BLV MA and NC are able to bind to nucleic acids; however, the viral assembly process and packaging of viral genomic RNA requires full-length Gag to produce infectious particles. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.036DOI Listing
February 2019
1 Read

Ensembles from Ordered and Disordered Proteins Reveal Similar Structural Constraints during Evolution.

J Mol Biol 2019 Feb 4. Epub 2019 Feb 4.

Departamento de Ciencia y Tecnología, CONICET, Universidad Nacional de Quilmes, Roque Sáenz Peña 352, B1876BXD, Bernal, Provincia de Buenos Aires, Argentina.

The conformations accessible to proteins are determined by the inter-residue interactions between amino acid residues. During evolution, structural constraints can exist that are required for protein function providing biologically relevant information. Here, we studied the proportion of sites evolving under structural constraints in two very different types of ensembles, those coming from ordered and disordered proteins. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.031DOI Listing
February 2019
1 Read

Rewiring of RSK-PDZ Interactome by Linear Motif Phosphorylation.

J Mol Biol 2019 Feb 3. Epub 2019 Feb 3.

Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary. Electronic address:

Phosphorylation of short linear peptide motifs is a widespread process for the dynamic regulation of protein-protein interactions. However, the global impact of phosphorylation events on the protein-protein interactome is rarely addressed. The disordered C-terminal tail of ribosomal S6 kinase 1 (RSK1) binds to PDZ domain-containing scaffold proteins, and it harbors a phosphorylatable PDZ binding motif (PBM) responsive to epidermal growth factor (EGF) stimulation. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.038DOI Listing
February 2019

Optogenetic Navigation of Routes Leading to Protein Amyloidogenesis in Bacteria.

Authors:
Rafael Giraldo

J Mol Biol 2019 Feb 2. Epub 2019 Feb 2.

Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas-CSIC, c/ Ramiro de Maeztu 9, E28040 Madrid, Spain. Electronic address:

Modulation of liquid-liquid and liquid-hydrogel phase transitions is central to avoid the cytotoxic aggregation of proteins in eukaryotic cells, but knowledge on its relevance in bacteria is limited. Here the power of optogenetics to engineer proteins as light-responsive switches has been used to control the balance between solubility and aggregation for LOV2-WH1, a chimera between the plant blue light-responsive domain LOV2 and the bacterial prion-like protein RepA-WH1. These proteins were first linked by fusing, as a continuous α-helix, the C-terminal photo-transducer Jα helix in LOV2 with the N-terminal domain-closure α1 helix in RepA-WH1, and then improved for light-responsiveness by including mutations in the Jα moiety. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.037DOI Listing
February 2019
1 Read

The Role of SurA PPIase Domains in Preventing Aggregation of the Outer-Membrane Proteins tOmpA and OmpT.

J Mol Biol 2019 Feb 1. Epub 2019 Feb 1.

Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address:

SurA is a conserved ATP-independent periplasmic chaperone involved in the biogenesis of outer-membrane proteins (OMPs). Escherichia coli SurA has a core domain and two peptidylprolyl isomerase (PPIase) domains, the role(s) of which remain unresolved. Here we show that while SurA homologues in early proteobacteria typically contain one or no PPIase domains, the presence of two PPIase domains is common in SurA in later proteobacteria, implying an evolutionary advantage for this domain architecture. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.032DOI Listing
February 2019

Conformational Dynamics of Damage Processing by Human DNA Glycosylase NEIL1.

J Mol Biol 2019 Feb 1. Epub 2019 Feb 1.

SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., Novosibirsk 630090, Russia; Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia. Electronic address:

Endonuclease VIII-like protein 1 (NEIL1) is a DNA repair enzyme found in higher eukaryotes, including humans. It belongs to the helix-two turn-helix (H2TH) structural superfamily together with Escherichia coli formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease VIII (Nei), and removes a variety of oxidized purine and pyrimidine bases from DNA. Structural, modeling and kinetic studies have established that the bacterial H2TH superfamily enzymes proceed through several conformational intermediates while recognizing and removing their cognate lesions. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.030DOI Listing
February 2019
1 Read

On the Mechanism and Origin of Isoleucyl-tRNA Synthetase Editing against Norvaline.

J Mol Biol 2019 Jan 31. Epub 2019 Jan 31.

Department of Chemistry, Faculty of Science, University of Zagreb, Zagreb 10000, Croatia. Electronic address:

Aminoacyl-tRNA synthetases (aaRSs), the enzymes responsible for coupling tRNAs to their cognate amino acids, minimize translational errors by intrinsic hydrolytic editing. Here, we compared norvaline (Nva), a linear amino acid not coded for protein synthesis, to the proteinogenic, branched valine (Val) in their propensity to mistranslate isoleucine (Ile) in proteins. We show that in the synthetic site of isoleucyl-tRNA synthetase (IleRS), Nva and Val are activated and transferred to tRNA at similar rates. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193004
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http://dx.doi.org/10.1016/j.jmb.2019.01.029DOI Listing
January 2019
2 Reads

The Double Life of Group B Streptococcus: Asymptomatic Colonizer and Potent Pathogen.

J Mol Biol 2019 Jan 31. Epub 2019 Jan 31.

Department of Global Health, University of Washington, Seattle 98195, WA, USA; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle 98101, WA, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle 98195, WA, USA. Electronic address:

Group B streptococcus (GBS) is a β-hemolytic gram-positive bacterium that colonizes the lower genital tract of approximately 18% of women globally as an asymptomatic member of the gastrointestinal and/or vaginal flora. If established in other host niches, however, GBS is highly pathogenic. During pregnancy, ascending GBS infection from the vagina to the intrauterine space is associated with preterm birth, stillbirth, and fetal injury. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.035DOI Listing
January 2019
2 Reads

Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease.

J Mol Biol 2019 Jan 31. Epub 2019 Jan 31.

German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, North Rhine-Westphalia, Germany. Electronic address:

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.034DOI Listing
January 2019

Progranulin Stimulates the In Vitro Maturation of Pro-Cathepsin D at Acidic pH.

J Mol Biol 2019 Jan 25. Epub 2019 Jan 25.

Department of Neurology, University of California, San Francisco, CA 94143, USA. Electronic address:

Single-copy loss-of-function mutations in the progranulin gene (PGRN) underlie the neurodegenerative disease frontotemporal lobar degeneration, while homozygous loss-of-function of PGRN results in the lysosomal storage disorder neuronal ceroid lipofuscinosis. Despite evidence that normal PGRN levels are critical for neuronal health, the function of this protein is not yet understood. Here, we show that PGRN stimulates the in vitro maturation of the lysosomal aspartyl protease cathepsin D (CTSD). Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.027DOI Listing
January 2019
2 Reads

Fast Translation within the First 45 Codons Decreases mRNA Stability and Increases Premature Transcription Termination in E. coli.

J Mol Biol 2019 Jan 25. Epub 2019 Jan 25.

Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK-2100 Copenhagen Ø, Denmark. Electronic address:

We show here that the specific use of fast or slowly translated codons in the early coding region of a gene may influence both the mRNA stability and premature transcription termination. We first inserted a pair of nearly identical 42 base pairs long sequences into codon 3 of the E. coli lacZ gene. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.026DOI Listing
January 2019

Extent and Origins of Functional Diversity in a Subfamily of Glycoside Hydrolases.

J Mol Biol 2019 Jan 25. Epub 2019 Jan 25.

Great Lakes Bioenergy Research Center, Madison, WI 53706 USA; Department of Biochemistry, University of Wisconsin, Madison, WI 53706 USA. Electronic address:

Some glycoside hydrolases have broad specificity for hydrolysis of glycosidic bonds, potentially increasing their functional utility and flexibility in physiological and industrial applications. To deepen the understanding of the structural and evolutionary driving forces underlying specificity patterns in glycoside hydrolase family 5, we quantitatively screened the activity of the catalytic core domains from subfamily 4 (GH5_4) and closely related enzymes on four substrates: lichenan, xylan, mannan, and xyloglucan. Phylogenetic analysis revealed that GH5_4 consists of three major clades, and one of these clades, referred to here as clade 3, displayed average specific activities of 4. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.024DOI Listing
January 2019
1 Read

Aggregation of Respiratory Complex Subunits Marks the Onset of Proteotoxicity in Proteasome Inhibited Cells.

J Mol Biol 2019 Jan 22. Epub 2019 Jan 22.

CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India. Electronic address:

Proteostasis is maintained by optimal expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. In this study, using quantitative proteomics and microscopy, we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein destabilization event during short-term proteasome inhibition. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.022DOI Listing
January 2019

A Cell-Surface GH9 Endo-Glucanase Coordinates with Surface Glycan-Binding Proteins to Mediate Xyloglucan Uptake in the Gut Symbiont Bacteroides ovatus.

J Mol Biol 2019 Jan 19. Epub 2019 Jan 19.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address:

Dietary fiber is an important food source for members of the human gut microbiome. Members of the dominant Bacteroidetes phylum capture diverse polysaccharides via the action of multiple cell surface proteins encoded within polysaccharide utilization loci (PUL). The independent activities of PUL-encoded glycoside hydrolases (GHs) and surface glycan-binding proteins (SGBPs) for the harvest of various glycans have been studied in detail, but how these proteins work together to coordinate uptake is poorly understood. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.008DOI Listing
January 2019

Recent Advances and Current Trends in Nucleotide Second Messenger Signaling in Bacteria.

J Mol Biol 2019 Jan 19. Epub 2019 Jan 19.

Institute of Microbiology, Leibniz-Universität Hannover, 30419 Hannover, Germany.

The "International Symposium on Nucleotide Second Messenger Signaling in Bacteria" (September 30-October 3, 2018, Berlin), which was organized within the framework of DFG Priority Programme 1879 (www.spp1879.de), brought together 125 participants from 20 countries to discuss recent progress and future trends in this field. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193001
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http://dx.doi.org/10.1016/j.jmb.2019.01.014DOI Listing
January 2019
6 Reads

Structure of hRpn10 Bound to UBQLN2 UBL Illustrates Basis for Complementarity between Shuttle Factors and Substrates at the Proteasome.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address:

The 26S proteasome is a highly complex 2.5-MDa molecular machine responsible for regulated protein degradation. Proteasome substrates are typically marked by ubiquitination for recognition at receptor sites contributed by Rpn1/S2/PSMD2, Rpn10/S5a, and Rpn13/Adrm1. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193003
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http://dx.doi.org/10.1016/j.jmb.2019.01.021DOI Listing
January 2019
3 Reads

A Nucleotide-Dependent Conformational Switch Controls the Polymerization of Human IMP Dehydrogenases to Modulate their Catalytic Activity.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Metabolic Engineering Group, Dpto. Microbiología y Genética, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain. Electronic address:

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades, but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193002
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http://dx.doi.org/10.1016/j.jmb.2019.01.020DOI Listing
January 2019
3 Reads

Tau Modulates VGluT1 Expression.

J Mol Biol 2019 Feb 18;431(4):873-884. Epub 2019 Jan 18.

Laboratory of Biology, BIO@SNS, Scuola Normale Superiore, Pisa, Italy. Electronic address:

Tau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.023DOI Listing
February 2019
2 Reads

The Role of MicroRNAs in Spinocerebellar Ataxia Type 3.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Department of Neurology, University of Bonn, Sigmund-Freud-Street 25, 53127 Bonn, Germany. Electronic address:

More than 90% of the human genome are transcribed as non-coding RNAs. While it is still under debate if all these non-coding transcripts are functional, there is emerging evidence that RNA has several important functions in addition to coding for proteins. For example, microRNAs (miRNAs) are important regulatory RNAs that control gene expression in various biological processes and human diseases. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.019DOI Listing
January 2019

Center Finding in E. coli and the Role of Mathematical Modeling: Past, Present and Future.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, United Kingdom. Electronic address:

We review the key role played by mathematical modeling in elucidating two center-finding patterning systems in Escherichia coli: midcell division positioning by the MinCDE system and DNA partitioning by the ParABS system. We focus particularly on how, despite much experimental effort, these systems were simply too complex to unravel by experiments alone, and instead required key injections of quantitative, mathematical thinking. We conclude the review by analyzing the frequency of modeling approaches in microbiology over time. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.017DOI Listing
January 2019
1 Read

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Neurula Laboratory, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia. Electronic address:

As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.018DOI Listing
January 2019
10 Reads

Role of Microglia in Ataxias.

J Mol Biol 2019 Jan 18. Epub 2019 Jan 18.

Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Microglia, the resident macrophages of the central nervous system, critically influence neural function during development and in adulthood. Microglia are also profoundly sensitive to insults to the brain to which they respond with process of activation that includes spectrum of changes in morphology, function, and gene expression. Ataxias are a class of neurodegenerative diseases characterized by motor discoordination and predominant cerebellar involvement. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193002
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http://dx.doi.org/10.1016/j.jmb.2019.01.016DOI Listing
January 2019
4 Reads

Cryo-EM Structure (4.5-Å) of Yeast Kinesin-5-Microtubule Complex Reveals a Distinct Binding Footprint and Mechanism of Drug Resistance.

J Mol Biol 2019 Feb 16;431(4):864-872. Epub 2019 Jan 16.

Institute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, UK. Electronic address:

Kinesin-5s are microtubule-dependent motors that drive spindle pole separation during mitosis. We used cryo-electron microscopy to determine the 4.5-Å resolution structure of the motor domain of the fission yeast kinesin-5 Cut7 bound to fission yeast microtubules and explored the topology of the motor-microtubule interface and the susceptibility of the complex to drug binding. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.011DOI Listing
February 2019

The Elusive Inhibitory Function of the Acidic N-Terminal Segment of the Prodomain of PCSK9: The Plot Thickens.

Authors:
Nabil G Seidah

J Mol Biol 2019 Jan 15. Epub 2019 Jan 15.

Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; affiliated to the University of Montreal), 110 Pine Ave West, Montreal, QC, Canada H2W 1R7. Electronic address:

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http://dx.doi.org/10.1016/j.jmb.2019.01.015DOI Listing
January 2019

Discovery and Characterization of FMN-Binding β-Glucuronidases in the Human Gut Microbiome.

J Mol Biol 2019 Jan 15. Epub 2019 Jan 15.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, and Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

The human gut microbiota encodes β-glucuronidases (GUSs) that play key roles in health and disease via the metabolism of glucuronate-containing carbohydrates and drugs. Hundreds of putative bacterial GUS enzymes have been identified by metagenomic analysis of the human gut microbiome, but less than 10% have characterized structures and functions. Here we describe a set of unique gut microbial GUS enzymes that bind flavin mononucleotide (FMN). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836193001
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http://dx.doi.org/10.1016/j.jmb.2019.01.013DOI Listing
January 2019
6 Reads

Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain.

J Mol Biol 2019 Jan 15. Epub 2019 Jan 15.

Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipid metabolism by degrading liver LDL receptors. Structural studies have provided molecular details of PCSK9 function. However, the N-terminal acidic stretch of the PCSK9 prodomain (Q31-T60) has eluded structural investigation, since it is in a disordered state. Read More

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http://dx.doi.org/10.1016/j.jmb.2018.11.025DOI Listing
January 2019
1 Read

Crystallographic Analysis of the Catalytic Mechanism of Phosphopantothenoylcysteine Synthetase from Saccharomyces cerevisiae.

J Mol Biol 2019 Feb 14;431(4):764-776. Epub 2019 Jan 14.

Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China. Electronic address:

Phosphopantothenoylcysteine (PPC) synthetase (PPCS) catalyzes nucleoside triphosphate-dependent condensation reaction between 4'-phosphopantothenate (PPA) and l-cysteine to form PPC in CoA biosynthesis. The catalytic mechanism of PPCS has not been resolved yet. Coenzyme A biosynthesis protein 2 (Cab2) possesses activity of PPCS in Saccharomyces cerevisiae. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.012DOI Listing
February 2019
1 Read

N-glycan Utilization by Bifidobacterium Gut Symbionts Involves a Specialist β-Mannosidase.

J Mol Biol 2019 Feb 11;431(4):732-747. Epub 2019 Jan 11.

Brazilian Bioethanol Science and Technology Laboratory (CTBE), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, Brazil. Electronic address:

Bifidobacteria represent one of the first colonizers of human gut microbiota, providing to this ecosystem better health and nutrition. To maintain a mutualistic relationship, they have enzymes to degrade and use complex carbohydrates non-digestible by their hosts. To succeed in the densely populated gut environment, they evolved molecular strategies that remain poorly understood. Read More

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http://dx.doi.org/10.1016/j.jmb.2018.12.017DOI Listing
February 2019
1 Read

NMR Investigation of the Interaction between the RecQ C-Terminal Domain of Human Bloom Syndrome Protein and G-Quadruplex DNA from the Human c-Myc Promoter.

J Mol Biol 2019 Feb 10;431(4):794-806. Epub 2019 Jan 10.

Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. Electronic address:

Bloom syndrome protein (BLM) is one of five human RecQ helicases that participate in DNA metabolism. RecQ C-terminal (RQC) domain is the main DNA binding module of BLM and specifically recognizes G-quadruplex (G4) DNA structures. Because G4 processing by BLM is essential for regulating replication and transcription, both G4 and BLM are considered as potential targets for anticancer therapy. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836183113
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http://dx.doi.org/10.1016/j.jmb.2019.01.010DOI Listing
February 2019
4 Reads

The Role of Connexins in Gastrointestinal Diseases.

J Mol Biol 2019 Feb 11;431(4):643-652. Epub 2019 Jan 11.

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, PR China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, PR China. Electronic address:

Gap junctions are hexagonal arrays of protein molecules in the plasma membrane and were first described in Mauthner cell synapses of goldfish. They form pathways for coupling between cells, allowing passive, electrotonic spread of ions and also passage of larger molecules such as amino acids and nucleotides. They are expressed in both excitable and non-excitable tissues. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00222836183106
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http://dx.doi.org/10.1016/j.jmb.2019.01.007DOI Listing
February 2019
6 Reads
4.333 Impact Factor

Crystal Structures of Csm2 and Csm3 in the Type III-A CRISPR-Cas Effector Complex.

J Mol Biol 2019 Feb 11;431(4):748-763. Epub 2019 Jan 11.

Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan. Electronic address:

Clustered regularly interspaced short palindromic repeat (CRISPR) loci and CRISPR-associated (Cas) genes encode CRISPR RNAs (crRNA) and Cas proteins, respectively, which play important roles in the adaptive immunity system (CRISPR-Cas system) in prokaryotes. The crRNA and Cas proteins form ribonucleoprotein effector complexes to capture and degrade invading genetic materials with base complementarity to the crRNA guide sequences. The Csm complex, a type III-A effector complex, comprises five Cas proteins (Csm1-Csm5) and a crRNA, which co-transcriptionally degrades invading DNA and RNA. Read More

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http://dx.doi.org/10.1016/j.jmb.2019.01.009DOI Listing
February 2019