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Journal of Molecular Biology

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https://www.readbyqxmd.com/read/28533135/enhanced-local-disorder-in-a-clinically-elusive-von-willebrand-factor-provokes-high-affinity-platelet-clumping
#1
Alexander Tischer, Venkata R Machha, Juan P Frontroth, Maria A Brehm, Tobias Obser, Reinhard Schneppenheim, Leland Mayne, S Walter Englander, Matthew Auton
Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP-treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing implicate an abnormal gain-of-function phenotype, evidenced by thrombocytopenia, that quickly relapses back to normal platelet counts and deficient plasma VWF. Using surface plasmon resonance, analytical rheology, and hydrogen-deuterium exchange mass spectrometry (HXMS), we decipher mechanisms of A1-GPIbα mediated platelet adhesion and resolve dynamic secondary structure elements that regulate the binding pathway...
May 19, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28527786/sumo-in-the-dna-double-stranded-break-response-similarities-differences-and-co-operation-with-ubiquitin
#2
REVIEW
Joanna R Morris, Alexander J Garvin
In recent years our knowledge of the varied role that ubiquitination plays in promoting signal amplification, novel protein interactions and protein turn-over has progressed rapidly. This is particularly remarkable in the examination of how DNA Double-Strand Breaks (DSBs) are repaired, with many components of the ubiquitin conjugation, de-conjugation and recognition machinery now identified as key factors in DSB repair. In addition, a member of the ubiquitin-like family, SUMO (Small Ubiquitin-like Modifier) has also been recognised as integral for efficient repair...
May 17, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28506636/multiple-dna-interactions-contribute-to-the-initiation-of-telomerase-elongation
#3
Ahu Karademir Andersson, Cecilia Gustafsson, Roopesh Krishnankutty, Marita Cohn
Telomerase maintains telomere length and chromosome integrity by adding short tandem repeats of single-stranded DNA to the 3' ends, via reverse transcription of a defined template region of its RNA subunit. To further understand the telomerase elongation mechanism, we studied the primer utilization and extension activity of the telomerase from the budding yeast Naumovozyma castellii (Saccharomyces castellii), which displays a processive nucleotide and repeat addition polymerization. For the efficient initiation of canonical elongation, telomerase required 4nt primer 3' end complementarity to the template RNA...
May 12, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28506635/cryoem-structure-of-an-influenza-virus-receptor-binding-site-antibody-antigen-interface
#4
Yuhang Liu, Junhua Pan, Simon Jenni, Donald D Raymond, Tim Caradonna, Khoi T Do, Aaron G Schmidt, Stephen C Harrison, Nikolaus Grigorieff
Structure-based vaccine design depends on extensive structural analyses of antigen-antibody complexes. Single-particle electron cryomicroscopy (cryoEM) can circumvent some of the problems of x-ray crystallography as a pipeline for obtaining the required structures. We have examined the potential of single-particle cryoEM for determining the structure of influenza-virus hemagglutinin (HA):single-chain Fv (scFv) complexes, by studying a complex we failed to crystallize in pursuing an extended project of the human immune response to influenza vaccines...
May 12, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28502794/mir-125a-5p-modulates-phenotypic-switch-of-vascular-smooth-muscle-cells-by-targeting-ets-1
#5
C Gareri, C Iaconetti, S Sorrentino, C Covello, S De Rosa, C Indolfi
MicroRNAs are key regulators of vascular smooth muscle cells (VSMCs) phenotypic switch, one of the main events responsible for bare metal stent restenosis (ISR) after percutaneous coronary intervention (PCI). miR-125a-5p is an important modulator of differentiation, proliferation and migration in different cell types; however, its role in VSMCs is still unknown. The aim of this study was to evaluate the role of miR-125a-5p in VSMCs phenotypic switch. Our results suggest that miR-125a-5p is highly expressed in VSMCs, but it is down-regulated after vascular injury in vivo...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28502793/salt-mediated-oligomerization-of-the-mouse-prion-protein-monitored-by-real-time-nmr
#6
Ishita Sengupta, Suhas H Bhate, Ranabir Das, Jayant B Udgaonkar
The prion protein forms ß-rich soluble oligomers in vitro at pH4 in the presence of physiological concentrations of salt. In the absence of salt, oligomerization and misfolding does not take place in an experimentally tractable timescale. While it is well established that a lowering of pH facilitates misfolding and oligomerization of this protein, the role of salt remains poorly understood. Here, solution-state NMR was used to probe perturbations in the monomeric mouse prion protein moPrP) structure immediately upon salt-addition, prior to the commencement of the oligomerization reaction...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28502792/drug-binding-poses-relate-structure-with-efficacy-in-the-%C3%AE-opioid-receptor
#7
Katy J Sutcliffe, Graeme Henderson, Eamonn Kelly, Richard B Sessions
The μ-opioid receptor (MOPr) is a clinically important G protein-coupled receptor (GPCR) which couples to Gi/o proteins and arrestins. At present the receptor conformational changes that occur following agonist binding and activation are poorly understood. This study has employed molecular dynamics simulations to investigate the binding mode and receptor conformational changes induced by structurally similar opioid ligands of widely differing intrinsic agonist efficacy, norbuprenorphine, buprenorphine and diprenorphine...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28502791/single-strand-consensus-sequencing-reveals-that-hiv-type-but-not-subtype-significantly-impacts-viral-mutation-frequencies-and-spectra
#8
Jonathan M O Rawson, Daryl M Gohl, Sean R Landman, Megan E Roth, Morgan E Meissner, Tara S Peterson, James S Hodges, Kenneth B Beckman, Louis M Mansky
A long-standing question of human immunodeficiency virus (HIV) genetic variation and evolution has been whether differences exist in mutation rate and/or mutation spectra among HIV types (i.e., HIV-1 versus HIV-2) as well as among HIV groups (i.e., HIV-1 groups M-P and HIV-2 groups A-H) and HIV-1 Group M subtypes (i.e., subtypes A-D, F-H, and J-K). To address this, a new single-strand consensus sequencing assay was developed for the determination of HIV mutation frequencies and spectra using the Illumina sequencing platform...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28501588/oligomeric-structure-of-anabaena-sensory-rhodopsin-in-a-lipid-bilayer-environment-by-combining-solid-state-nmr-and-long-range-deer-constraints
#9
Sergey Milikisiyants, Shenlin Wang, Rachel A Munro, Matthew Donohue, Meaghan E Ward, David Bolton, Leonid S Brown, Tatyana I Smirnova, Vladimir Ladizhansky, Alex I Smirnov
Oligomerization of membrane proteins is common in nature. Here, we combine spin-labeling Double Electron-Electron Resonance (DEER) and solid-state NMR (ssNMR) spectroscopy to refine the structure of an oligomeric integral membrane protein, Anabaena Sensory Rhodopsin (ASR), reconstituted in a lipid environment. An essential feature of such a combined approach is that it provides structural distance restraints spanning a range of ca. 3-60Å, while using the same sample preparation (i.e., mutations, paramagnetic labeling, and reconstitution in lipid bilayers) for both ssNMR and DEER...
May 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28501587/functional-requirements-for-djla-and-rraa-mediated-enhancement-of-recombinant-membrane-protein-production-in-the-engineered-escherichia-coli-strains-suptoxd-and-suptoxr
#10
Dimitra Gialama, Dafni Chrysanthi Delivoria, Myrsini Michou, Artemis Giannakopoulou, Georgios Skretas
In previous work, we have generated the engineered Escherichia coli strains SuptoxD and SuptoxR, which upon co-expression of the effector genes djlA or rraA, respectively, are capable of suppressing the cytotoxicity caused by membrane protein (MP) overexpression and producing dramatically enhanced yields for a variety of recombinant MPs of both prokaryotic and eukaryotic origin. Here, we investigated the functional requirements for DjlA- and RraA-mediated enhancement of recombinant MP production in these strains and show that: (i) DjlA and RraA act independently, i...
May 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28501586/structural-molecular-biology-a-personal-reflection-on-the-occasion-of-john-kendrew-s-100th-birthday
#11
Patrick Cramer
Here I discuss the development and future of structural molecular biology, concentrating on the eukaryotic transcription machinery, and reflecting on John Kendrew's legacy from a personal perspective.
May 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28501585/proteolytic-post-translational-processing-of-adhesins-in-the-plant-pathogen-spiroplasma-citri
#12
Marie-Pierre Dubrana, Julia Guéguéniat, Clothilde Bertin, Sybille Duret, Nathalie Arricau-Bouvery, Stéphane Claverol, Carole Lartigue, Alain Blanchard, Joël Renaudin, Laure Béven
Mollicutes, including mycoplasmas and spiroplasmas have been considered as good representatives of the « minimal cell » concept: these wall-less bacteria are small in size, possess a minimal genome, and restricted metabolic capacities. However the recent discovery of the presence of post-translational modifications unknown so far, such as the targeted processing of membrane proteins of mycoplasma pathogens for human and swine, revealed a part of the hidden complexity of these microorganisms. In this study, we show that in the phytopathogen, insect-vectored, Spiroplasma citri ScARPs adhesins are post-translationally processed through an ATP-dependent targeted cleavage...
May 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28483649/effect-of-nascent-peptide-steric-bulk-on-elongation-kinetics-in-the-ribosome-exit-tunnel
#13
Pengse Po, Erin Delaney, Howard Gamper, Miklos Szanti-Kis, Lee Speight, LiWei Tu, Andrey Kosolapov, E James Petersson, Ya-Ming Hou, Carol Deutsch
All proteins are synthesized by the ribosome, a macromolecular complex that accomplishes the life-sustaining tasks of faithfully decoding mRNA and catalyzing peptide bond formation at the peptidyl transferase center (PTC). The ribosome has evolved an exit tunnel to host the elongating new peptide, protect it from proteolytic digestion, and guide its emergence. It is here that the nascent chain begins to fold. This folding process depends on the rate of translation at the PTC. We report here that, besides PTC events, translation kinetics depend on steric constraints on nascent peptide side chains, and that confined movements of cramped side chains within and through the tunnel fine-tune elongation rates...
May 5, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28483648/oleic-acid-induces-mir-7-processing-through-remodelling-of-pri-mir-7-protein-complex
#14
Santosh Kumar, Angela Downie Ruiz Velasco, Gracjan Michlewski
MicroRNAs (miRs) play a vital role in governing cell function, with their levels tightly controlled at transcriptional and post-transcriptional levels. Different sets of RNA-binding proteins (RNA-BPs) interact with primary (pri-) miRs and precursor (pre-) miR transcripts, controlling their biogenesis post-transcriptionally. The Hu antigen R (HuR)-mediated binding of Musashi homolog2 (MSI2) to the Conserved Terminal Loop (CTL) of pri-miR-7 regulates the levels of brain-enriched miR-7 formation in a tissue specific manner...
May 5, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28483647/telomerase-elongation-cycle-clues-from-dna-sequence-variations
#15
Sriram Vijayraghavan
No abstract text is available yet for this article.
May 5, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28479091/family-wide-comparative-analysis-of-cytidine-and-methylcytidine-deamination-by-eleven-human-apobec-proteins
#16
Fumiaki Ito, Yang Fu, Shen-Chi A Kao, Hanjing Yang, Xiaojiang S Chen
APOBECs are a family of cytidine deaminases involved in various important biological processes such as antibody diversification/maturation, restriction of viral infection, and generation of somatic mutations. Catalytically active APOBEC proteins execute their biological functions mostly through deaminating cytosine (C) to uracil on ssDNA/RNA. Activation-induced cytidine deaminase (AID), one of the APOBEC members, was reported to deaminate methylated cytosine (mC) on DNA and this mC deamination was proposed to be involved in demethylation of mC for epigenetic regulation...
May 4, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28478285/determinants-of-helix-formation-for-a-kv1-3-transmembrane-segment-inside-the-ribosome-exit-tunnel
#17
LiWei Tu, Carol Deutsch
Proteins begin to fold in the ribosome and misfolding has pathological consequences. Among the earliest folding events in biogenesis is the formation of a helix, an elementary structure that is ubiquitously present and required for correct protein folding in all proteomes. The determinants underlying helix formation in the confined space of the ribosome exit tunnel are relatively unknown. We chose the second transmembrane segment, S2, of a voltage-gated potassium channel, Kv1.3, as a model to probe this issue...
May 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28478284/comprehensive-identification-of-nuclear-and-cytoplasmic-tnrc6a-associating-proteins
#18
Masataka Suzawa, Kentaro Noguchi, Kenji Nishi, Hiroko Kozuka-Hata, Masaaki Oyama, Kumiko Ui-Tei
Trinucleotide repeat-containing gene 6A protein (TNRC6A) is an essential protein for microRNA-mediated gene silencing. TNRC6A functions in the cytoplasm as a platform protein interacting with Argonaute protein, on which microRNA is loaded for RNA silencing, and decapping enzymes or deadenylation protein complexes to induce mRNA degradation. We previously revealed that TNRC6A shuttles between the cytoplasm and nucleus. However, the function of TNRC6A in the nucleus is unclear. Here, we performed a comprehensive identification of the nuclear and cytoplasmic interacting proteins of TNRC6A protein by mass spectrometry and identified multiple proteins involved in the nuclear and cytoplasmic complexes...
May 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28478283/exploiting-synthetic-lethality-and-network-biology-to-overcome-egfr-inhibitor-resistance-in-lung-cancer
#19
REVIEW
Simon Vyse, Annie Howitt, Paul H Huang
Despite the recent approval of third generation therapies, overcoming resistance to Epidermal Growth Factor Receptor (EGFR) inhibitors remains a major challenge in non-small cell lung cancer (NSCLC). Conceptually, synthetic lethality holds the promise of identifying non-intuitive targets for tackling both acquired and intrinsic resistance in this setting. However, translating these laboratory findings into effective clinical strategies continues to be elusive. Here we provide an overview of the synthetic lethal approaches that have been employed to study EGFR inhibitor resistance and review the oncogene and non-oncogene signalling mechanisms which have thus far been unveiled by synthetic lethality screens...
May 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28478282/prokaryotic-ubiquitin-like-protein-and-its-ligase-deligase-enyzmes
#20
REVIEW
Cyrille L Delley, Andreas Müller, Michal Ziemski, Eilika Weber-Ban
Prokaryotic ubiquitin-like protein (Pup) and the modification enzymes involved in attaching Pup to or removing it from target proteins present a fascinating example of convergent evolution with respect to eukaryotic ubiquitination. Like ubiquitin (Ub), Pup is a small protein that can be covalently attached to lysine side chains of cellular proteins, and like Ub it can serve to recruit tagged proteins for proteasomal degradation. However, unlike Ub, Pup is conformationally highly dynamic, exhibits a different linkage connectivity to its target lysines and its ligase belongs to a different class of enzymes than the E1/E2/E3 cascade of ubiquitination...
May 3, 2017: Journal of Molecular Biology
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