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https://www.readbyqxmd.com/read/29136098/sequential-search-leads-to-faster-more-efficient-fragment-based-de-novo-protein-structure-prediction
#1
Saulo H P de Oliveira, Eleanor C Law, Jiye Shi, Charlotte M Deane
Motivation: Most current de novo structure prediction methods randomly sample protein conformations and thus require large amounts of computational resource. Here, we consider a sequential sampling strategy, building on ideas from recent experimental work which shows that many proteins fold cotranslationally. Results: We have investigated whether a pseudo-greedy search approach, which begins sequentially from one of the termini, can improve the performance and accuracy of de novo protein structure prediction...
November 9, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29080176/analysis-of-cotranslational-polyamine-sensing-during-decoding-of-odc-antizyme-mrna
#2
R Palanimurugan, Daniela Gödderz, Leo Kurian, R Jürgen Dohmen
Polyamines are essential poly-cations with vital functions in all cellular systems. Their levels are controlled by intricate regulatory feedback mechanisms. Abnormally high levels of polyamines have been linked to cancer. A rate-limiting enzyme in the biosynthesis of polyamines in fungi and higher eukaryotes is ornithine-decarboxylase (ODC). Its levels are largely controlled posttranslationally via ubiquitin-independent degradation mediated by ODC antizyme (OAZ). The latter is a critical polyamine sensor in a feedback control mechanism that adjusts cellular polyamine levels...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29073068/evidence-of-evolutionary-selection-for-cotranslational-folding
#3
William M Jacobs, Eugene I Shakhnovich
Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from cotranslational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for cotranslational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29057042/apratoxin-s10-a-dual-inhibitor-of-angiogenesis-and-cancer-cell-growth-to-treat-highly-vascularized-tumors
#4
Weijing Cai, Qi-Yin Chen, Long H Dang, Hendrik Luesch
Renal, hepatocellular, and neuroendocrine carcinomas are known as highly vascularized tumors. Although vascular endothelial growth factor A (VEGF-A)-targeted therapies have shown efficacy in the treatment of these cancers, drug resistance is a major concern and might be mediated by interleukin 6 (IL-6). Furthermore, upon antiangiogenic drug exposure, tumor cells may adapt to survive in a vascular-independent manner. Apratoxins are potent marine-derived cytotoxic in vivo-active agents, preventing cotranslational translocation in the secretory pathway, and show promise to overcome resistance by targeting angiogenesis and tumor growth simultaneously...
October 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29038496/the-hsp70-homolog-ssb-affects-ribosome-biogenesis-via-the-torc1-sch9-signaling-pathway
#5
Kaivalya Mudholkar, Edith Fitzke, Claudia Prinz, Matthias P Mayer, Sabine Rospert
The Hsp70 Ssb serves a dual role in de novo protein folding and ribosome biogenesis; however, the mechanism by which Ssb affects ribosome production is unclear. Here we establish that Ssb is causally linked to the regulation of ribosome biogenesis via the TORC1-Sch9 signaling pathway. Ssb is bound to Sch9 posttranslationally and required for the TORC1-dependent phosphorylation of Sch9 at T737. Also, Sch9 lacking phosphorylation at T737 displays significantly reduced kinase activity with respect to targets involved in the regulation of ribosome biogenesis...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28972538/mutations-in-signal-recognition-particle-srp54-cause-syndromic-neutropenia-with-shwachman-diamond-like-features
#6
Raphael Carapito, Martina Konantz, Catherine Paillard, Zhichao Miao, Angélique Pichot, Magalie S Leduc, Yaping Yang, Katie L Bergstrom, Donald H Mahoney, Deborah L Shardy, Ghada Alsaleh, Lydie Naegely, Aline Kolmer, Nicodème Paul, Antoine Hanauer, Véronique Rolli, Joëlle S Müller, Elisa Alghisi, Loïc Sauteur, Cécile Macquin, Aurore Morlon, Consuelo Sebastia Sancho, Patrizia Amati-Bonneau, Vincent Procaccio, Anne-Laure Mosca-Boidron, Nathalie Marle, Naël Osmani, Olivier Lefebvre, Jacky G Goetz, Sule Unal, Nurten A Akarsu, Mirjana Radosavljevic, Marie-Pierre Chenard, Fanny Rialland, Audrey Grain, Marie-Christine Béné, Marion Eveillard, Marie Vincent, Julien Guy, Laurence Faivre, Christel Thauvin-Robinet, Julien Thevenon, Kasiani Myers, Mark D Fleming, Akiko Shimamura, Elodie Bottollier-Lemallaz, Eric Westhof, Claudia Lengerke, Bertrand Isidor, Seiamak Bahram
Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa)...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28957655/analysis-of-ribosome-stalling-and-translation-elongation-dynamics-by-deep-learning
#7
Sai Zhang, Hailin Hu, Jingtian Zhou, Xuan He, Tao Jiang, Jianyang Zeng
Ribosome stalling is manifested by the local accumulation of ribosomes at specific codon positions of mRNAs. Here, we present ROSE, a deep learning framework to analyze high-throughput ribosome profiling data and estimate the probability of a ribosome stalling event occurring at each genomic location. Extensive validation tests on independent data demonstrated that ROSE possessed higher prediction accuracy than conventional prediction models, with an increase in the area under the receiver operating characteristic curve by up to 18...
September 27, 2017: Cell Systems
https://www.readbyqxmd.com/read/28946879/contribution-of-single-amino-acid-and-codon-substitutions-to-the-production-and-secretion-of-a-lipase-by-bacillus-subtilis
#8
Pia Skoczinski, Kristina Volkenborn, Alexander Fulton, Anuseema Bhadauriya, Christina Nutschel, Holger Gohlke, Andreas Knapp, Karl-Erich Jaeger
BACKGROUND: Bacillus subtilis produces and secretes proteins in amounts of up to 20 g/l under optimal conditions. However, protein production can be challenging if transcription and cotranslational secretion are negatively affected, or the target protein is degraded by extracellular proteases. This study aims at elucidating the influence of a target protein on its own production by a systematic mutational analysis of the homologous B. subtilis model protein lipase A (LipA). We have covered the full natural diversity of single amino acid substitutions at 155 positions of LipA by site saturation mutagenesis excluding only highly conserved residues and qualitatively and quantitatively screened about 30,000 clones for extracellular LipA production...
September 25, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28928132/seca-mediates-cotranslational-targeting-and-translocation-of-an-inner-membrane-protein
#9
Shuai Wang, Chien-I Yang, Shu-Ou Shan
Protein targeting to the bacterial plasma membrane was generally thought to occur via two major pathways: cotranslational targeting by signal recognition particle (SRP) and posttranslational targeting by SecA and SecB. Recently, SecA was found to also bind ribosomes near the nascent polypeptide exit tunnel, but the function of this SecA-ribosome contact remains unclear. In this study, we show that SecA cotranslationally recognizes the nascent chain of an inner membrane protein, RodZ, with high affinity and specificity...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28924459/genetic-code-optimization-for-cotranslational-protein-folding-codon-directional-asymmetry-correlates-with-antiparallel-betasheets-trna-synthetase-classes
#10
Hervé Seligmann, Ganesh Warthi
A new codon property, codon directional asymmetry in nucleotide content (CDA), reveals a biologically meaningful genetic code dimension: palindromic codons (first and last nucleotides identical, codon structure XZX) are symmetric (CDA = 0), codons with structures ZXX/XXZ are 5'/3' asymmetric (CDA = - 1/1; CDA = - 0.5/0.5 if Z and X are both purines or both pyrimidines, assigning negative/positive (-/+) signs is an arbitrary convention). Negative/positive CDAs associate with (a) Fujimoto's tetrahedral codon stereo-table; (b) tRNA synthetase class I/II (aminoacylate the 2'/3' hydroxyl group of the tRNA's last ribose, respectively); and (c) high/low antiparallel (not parallel) betasheet conformation parameters...
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/28917045/radioactive-75-se-labeling-and-detection-of-selenoproteins
#11
Sun Hee Yim, Ryuta Tobe, Anton A Turanov, Bradley A Carlson
The trace element selenium (Se) is incorporated into proteins as the amino acid selenocysteine (Sec), which is cotranslationally inserted into specific proteins in response to a UGA codon. Proteins containing Sec at these specific positions are called selenoproteins. Most selenoproteins function as oxidoreductases, while some serve other important functions. There are 25 known selenoprotein genes in humans and 24 in mice. The use of Sec allows selenoproteins to be detected by a convenient method involving metabolic labeling with (75)Se...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28865429/a-new-and-updated-resource-for-codon-usage-tables
#12
John Athey, Aikaterini Alexaki, Ekaterina Osipova, Alexandre Rostovtsev, Luis V Santana-Quintero, Upendra Katneni, Vahan Simonyan, Chava Kimchi-Sarfaty
BACKGROUND: Due to the degeneracy of the genetic code, most amino acids can be encoded by multiple synonymous codons. Synonymous codons naturally occur with different frequencies in different organisms. The choice of codons may affect protein expression, structure, and function. Recombinant gene technologies commonly take advantage of the former effect by implementing a technique termed codon optimization, in which codons are replaced with synonymous ones in order to increase protein expression...
September 2, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28853924/regulation-by-3-untranslated-regions
#13
Christine Mayr
3'-untranslated regions (3'-UTRs) are the noncoding parts of mRNAs. Compared to yeast, in humans, median 3'-UTR length has expanded approximately tenfold alongside an increased generation of alternative 3'-UTR isoforms. In contrast, the number of coding genes, as well as coding region length, has remained similar. This suggests an important role for 3'-UTRs in the biology of higher organisms. 3'-UTRs are best known to regulate diverse fates of mRNAs, including degradation, translation, and localization, but they can also function like long noncoding or small RNAs, as has been shown for whole 3'-UTRs as well as for cleaved fragments...
August 30, 2017: Annual Review of Genetics
https://www.readbyqxmd.com/read/28750053/comprehensive-structural-analysis-of-designed-incomplete-polypeptide-chains-of-the-replicase-nonstructural-protein-1-from-the-severe-acute-respiratory-syndrome-coronavirus
#14
Leonardo Vazquez, Luis Mauricio Trambaioli da Rocha E Lima, Marcius da Silva Almeida
The cotranslational folding is recognized as a very cooperative process that occurs after the nearly completion of the polypeptide sequence of a domain. Here we investigated the challenges faced by polypeptide segments of a non-vectorial β-barrel fold. Besides the biological interest behind the SARS coronavirus non-structural protein 1 (nsp1, 117 amino acids), this study model has two structural features that motivated its use in this work: 1- its recombinant production is dependent on the temperature, with greater solubility when expressed at low temperatures...
2017: PloS One
https://www.readbyqxmd.com/read/28713376/myristoylation-an-important-protein-modification-in-the-immune-response
#15
REVIEW
Daniel Ikenna Udenwobele, Ruey-Chyi Su, Sara V Good, Terry Blake Ball, Shailly Varma Shrivastav, Anuraag Shrivastav
Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins. The ubiquitous eukaryotic enzyme, N-myristoyltransferase, catalyzes the myristoylation process. Precisely, attachment of a myristoyl group increases specific protein-protein interactions leading to subcellular localization of myristoylated proteins with its signaling partners. The birth of the field of myristoylation, a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and more recently immune function...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28698365/stable-membrane-orientations-of-small-dual-topology-membrane-proteins
#16
Nir Fluman, Victor Tobiasson, Gunnar von Heijne
The topologies of α-helical membrane proteins are generally thought to be determined during their cotranslational insertion into the membrane. It is typically assumed that membrane topologies remain static after this process has ended. Recent findings, however, question this static view by suggesting that some parts of, or even the whole protein, can reorient in the membrane on a biologically relevant time scale. Here, we focus on antiparallel homo- or heterodimeric small multidrug resistance proteins and examine whether the individual monomers can undergo reversible topological inversion (flip flop) in the membrane until they are trapped in a fixed orientation by dimerization...
July 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28564553/structural-and-mechanistic-insights-into-protein-translocation
#17
Tom A Rapoport, Long Li, Eunyong Park
Many proteins are translocated across the endoplasmic reticulum (ER) membrane in eukaryotes or the plasma membrane in prokaryotes. These proteins use hydrophobic signal sequences or transmembrane (TM) segments to trigger their translocation through the protein-conducting Sec61/SecY channel. Substrates are first directed to the channel by cytosolic targeting factors, which use hydrophobic pockets to bind diverse signal and TM sequences. Subsequently, these hydrophobic sequences insert into the channel, docking into a groove on the outside of the lateral gate of the channel, where they also interact with lipids...
October 6, 2017: Annual Review of Cell and Developmental Biology
https://www.readbyqxmd.com/read/28516953/signal-recognition-particle-prevents-n-terminal-processing-of-bacterial-membrane-proteins
#18
Amitabh Ranjan, Evan Mercier, Arshiya Bhatt, Wolfgang Wintermeyer
Bacterial proteins are synthesized with an N-formylated amino-terminal methionine, and N-formylated peptides elicit innate-immunity responses against bacterial infections. However, the source of these formylated peptides is not clear, as most bacterial proteins are co-translationally deformylated by peptide deformylase. Here we develop a deformylation assay with translating ribosomes as substrates, to show that the binding of the signal recognition particle (SRP) to signal sequences in nascent proteins on the ribosome prevents deformylation, whereas deformylation of nascent proteins without signal sequence is not affected...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28507157/translation-and-folding-of-single-proteins-in-real-time
#19
Florian Wruck, Alexandros Katranidis, Knud H Nierhaus, Georg Büldt, Martin Hegner
Protein biosynthesis is inherently coupled to cotranslational protein folding. Folding of the nascent chain already occurs during synthesis and is mediated by spatial constraints imposed by the ribosomal exit tunnel as well as self-interactions. The polypeptide's vectorial emergence from the ribosomal tunnel establishes the possible folding pathways leading to its native tertiary structure. How cotranslational protein folding and the rate of synthesis are linked to a protein's amino acid sequence is still not well defined...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28494952/fast-protein-translation-can-promote-co-and%C3%A2-posttranslational-folding-of-misfolding-prone-proteins
#20
Fabio Trovato, Edward P O'Brien
Chemical kinetic modeling has previously been used to predict that fast-translating codons can enhance cotranslational protein folding by helping to avoid misfolded intermediates. Consistent with this prediction, protein aggregation in yeast and worms was observed to increase when translation was globally slowed down, possibly due to increased cotranslational misfolding. Observation of similar behavior in molecular simulations would confirm predictions from the simpler chemical kinetic model and provide a molecular perspective on cotranslational folding, misfolding, and the impact of translation speed on these processes...
May 9, 2017: Biophysical Journal
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