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Mahmood Haj-Yahya, Hilal A Lashuel
The microtubule-associated protein Tau plays a central role in neurodegeneration and is a leading therapeutic target for the treatment of Alzheimer's disease (AD). Several lines of evidence suggest that post-translational modifications (PTMs) regulate the function(s) of Tau, including its subcellular localization, clearance, aggregation, toxicity, and pathology spreading. However, the lack of tools and methodologies that allow site-specific introduction of PTMs in Tau have limited our ability to dissect the role of PTMs in regulating Tau functions in health and disease...
April 23, 2018: Journal of the American Chemical Society
Lei Wei, Jesse G Meyer, Birgit Schilling
Post-translational modification (PTM) of protein lysine residues by NƐ-acylation induces structural changes that can dynamically regulate protein functions, for example, by changing enzymatic activity or by mediating interactions. Precise quantification of site-specific protein acylation occupancy, or stoichiometry, is essential for understanding the functional consequences of both global low-level stoichiometry and individual high-level acylation stoichiometry of specific lysine residues. Other groups have reported measurement of lysine acetylation stoichiometry by comparing the ratio of peptide precursor isotopes from endogenous, natural abundance acylation and exogenous, heavy isotope-labeled acylation introduced after quantitative chemical acetylation of proteins using stable isotope-labeled acetic anhydride...
April 4, 2018: Journal of Visualized Experiments: JoVE
Lunxi Liang, Huanbin Wang, Hubing Shi, Zhaoli Li, Han Yao, Zhigao Bu, Ningning Song, Chushu Li, Dabin Xiang, Yao Zhang, Jilin Wang, Ye Hu, Qi Xu, Yanlei Ma, Zhongyi Cheng, Yingchao Wang, Shuliang Zhao, Jin Qian, Yingxuan Chen, Jing-Yuan Fang, Jie Xu
Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53...
April 10, 2018: Cell Chemical Biology
Ching-Yu Lin, Jau-Jiuan Sheu, I-Shih Tsai, Sen-Te Wang, Li-Yu Yang, I-Uen Hsu, Hui-Wen Chang, Horng-Mo Lee, Shu-Huei Kao, Ching-Kuo Lee, Chien-Ho Chen, Yung-Feng Lin
OBJECTIVE: Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis. METHODS: Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses...
April 19, 2018: Clinical Biochemistry
Evan W McConnell, Emily G Werth, Leslie M Hicks
Post-translational modifications (PTMs) are covalent modifications to protein residues which may alter both conformation and activity, thereby modulating signaling and metabolic processes. While PTMs have been largely investigated independently, examination into how different modification interact, or crosstalk, will reveal a more complete understanding of the reciprocity of signaling cascades across numerous pathways. Combinatorial reversible thiol oxidation and phosphorylation in eukaryotes is largely recognized, but rigorous approaches for experimental discovery are underdeveloped...
April 4, 2018: Redox Biology
Kaixian Zhu, Ramon Farre, Ira Katz, Sébastien Hardy, Pierre Escourrou
The upper airway (UA) in humans is commonly modeled as a Starling resistor. However, negative effort dependence (NED) observed in some patients with obstructive sleep apnea (OSA) contradicts predictions based on the Starling resistor model in which inspiratory flow is independent of inspiratory driving pressure when flow is limited. In a respiratory bench model consisting of a collapsible tube and an active lung model (ASL5000), inspiratory flow characteristics were investigated in relation to upstream, downstream and extra-luminal pressures (denoted as Pus, Pds and Pout, respectively) by varying inspiratory effort (muscle pressure) from -1 to -20 cmH2 O in the active lung...
April 19, 2018: Journal of Applied Physiology
Marta Baroncelli, Bram C J van der Eerden, Siddharth Chatterji, Enrique Rull Trinidad, Yik Y Kan, Marijke Koedam, Ingmar A J van Hengel, Rodrigo D A M Alves, Lidy E Fratila-Apachitei, Jeroen A A Demmers, Jeroen van de Peppel, Johannes Ptm van Leeuwen
Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is crucial to accelerate bone formation. In this context, the use of extracellular matrix (ECM) as natural 3D-framework mimicking in vivo tissue architecture is of interest. The aim of this study was to generate a devitalized human osteogenic MSC-derived ECM and to investigate its impact on MSC osteogenic differentiation to improve MSC properties in bone regeneration. The devitalized ECM significantly enhanced MSC adhesion and proliferation...
April 18, 2018: Tissue Engineering. Part A
Vivian Hook, Christopher B Lietz, Sonia Podvin, Tomas Cajka, Oliver Fiehn
Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications...
April 17, 2018: Journal of the American Society for Mass Spectrometry
A J Garcia-Prats, E M Svensson, E D Weld, H S Schaaf, A C Hesseling
After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
Yathish H M, Subodh Kumar, Rajni Chaudhary, Chinmoy Mishra, Sivakumar A, Amit Kumar, Anuj Chauhan, S K Ghosh, Abhijit Mitra
Protamines (PRMs), important proteins of chromatin condensation in spermiogenesis, are promising candidate genes to explore markers of sperm motility. The coding and in-silico predicted promoter regions of these genes were investigated in 102 crossbred and 32 purebred cattle. Also, mRNA quantification was done to explore its possibility as diagnostic tool of infertility. The PCR-SSCP analysis indicated there were two band patterns only in fragment I of the PRM1 and fragment II of the PRM2 gene. The sequence analysis revealed A152G and G179A transitions in the PRM1 gene...
April 10, 2018: Animal Reproduction Science
Stephanie A Beach, Linda H Doerrer
As the scale of microelectronic circuit devices approaches the atomic limit, the study of molecular-based wires and magnets has become more prevalent. Compounds with quasi-1D geometries have been investigated for their electronic conductivity and magnetic properties with potential use as nanoscale circuit components and information storage devices. To increase the number of compositionally tailored molecular systems available to study, we have taken a building-block, bottom-up approach to the development of improved electronic structure and magnetic properties of quasi-1D arrays...
April 13, 2018: Accounts of Chemical Research
Emma A Morrison, Samuel Bowerman, Kelli L Sylvers, Jeff Wereszczynski, Catherine A Musselman
Histone tails harbor a plethora of post-translational modifications that direct the function of chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments of histone tails. Here, we extend these studies into the nucleosome context and find that the conformation adopted by the histone H3 tails is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy and MD simulations, we show that the H3 tails interact robustly but dynamically with nucleosomal DNA, substantially reducing PHD finger association...
April 12, 2018: ELife
Felix Wojcik, Geoffrey P Dann, Leslie Y Beh, Galia T Debelouchina, Raphael Hofmann, Tom W Muir
Ubiquitylation of histone H2B at lysine residue 120 (H2BK120ub) is a prominent histone posttranslational modification (PTM) associated with the actively transcribed genome. Although H2BK120ub triggers several critical downstream histone modification pathways and changes in chromatin structure, less is known about the regulation of the ubiquitylation reaction itself, in particular with respect to the modification status of the chromatin substrate. Here we employ an unbiased library screening approach to profile the impact of pre-existing chromatin modifications on de novo ubiquitylation of H2BK120 by the cognate human E2:E3 ligase pair, UBE2A:RNF20/40...
April 11, 2018: Nature Communications
Jianhong Zhou, Suwen Zhao, A Keith Dunker
Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP-AS-PTM toolkit...
April 4, 2018: Journal of Molecular Biology
Wolfgang Skala, Therese Wohlschlager, Stefan Senn, Gabriel E Huber, Christian G Huber
Hybrid mass spectrometry (MS) is an emerging technique for characterizing glycoproteins, which typically display pronounced microheterogeneity. Since hybrid MS combines information from different experimental levels, it crucially depends on computational methods. Here, we describe a novel software tool, MoFi, which integrates hybrid MS data to assign glycans and other post-translational modifications (PTMs) in deconvoluted mass spectra of intact proteins. Its two-stage search algorithm first assigns monosaccharide/PTM compositions to each peak and then compiles a hierarchical list of glycan combinations compatible with these compositions...
April 6, 2018: Analytical Chemistry
Aleš Holfeld, Alberto Valdés, Per-Uno Malmström, Ulrika Segersten, Sara Bergström Lind
Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT)-embedded and frozen tissue specimens in biobanks are highly valuable in clinical studies but proteomic and post-translational modification (PTM) studies using mass spectrometry (MS) have been limited due to structural arrangement of proteins and contaminations from embedding material. This study aims to develop a parallel proteomic workflow for FFPE and OCT/frozen samples that allows for large-scale, quick, reproducible, qualitative, and quantitative high-resolution MS analysis...
April 13, 2018: Analytical Chemistry
Simon Veyron, Gérald Peyroche, Jacqueline Cherfils
During the last decade, FIC proteins have emerged as a large family comprised of a variety of bacterial enzymes and a single member in animals. The air de famille of FIC proteins stems from a domain of conserved structure, which catalyzes the post-translational modification of proteins (PTM) by a phosphate-containing compound. In bacteria, examples of FIC proteins include the toxin component of toxin/antitoxin modules, such as Doc-Phd and VbhT-VbhA, toxins secreted by pathogenic bacteria to divert host cell processes, such as VopS, IbpA and AnkX, and a vast majority of proteins of unknown functions...
March 1, 2018: Pathogens and Disease
Anne Witzky, Katherine R Hummels, Rodney Tollerson, Andrei Rajkovic, Lisa A Jones, Daniel B Kearns, Michael Ibba
Elongation factor P (EF-P) is a ubiquitous translation factor that facilitates translation of polyproline motifs. In order to perform this function, EF-P generally requires posttranslational modification (PTM) on a conserved residue. Although the position of the modification is highly conserved, the structure can vary widely between organisms. In Bacillus subtilis , EF-P is modified at Lys32 with a 5-aminopentanol moiety. Here, we use a forward genetic screen to identify genes involved in 5-aminopentanolylation...
April 3, 2018: MBio
Xiyang Liu, Zhenqi Chen
OBJECTIVE: To identify the effects of palate repair on cranial base and maxillary morphology in patients with unilateral cleft lip and palate (UCLP) and to discover the relevance between cranial base and maxilla through cephalometric analysis. DESIGN: Retrospective. PATIENTS: Thirty-seven UCLP patients with operated lip (OL) and unoperated palate constituted OL group and were classified into 5 cervical vertebral maturation (CVM) stages. Thirty-seven UCLP patients with operated lip and palate (OLP) and 37 noncleft people with skeletal class I malocclusion were CVM- and sex-matched with the OL group as OLP group and control group, respectively...
January 1, 2018: Cleft Palate-craniofacial Journal
Indranil De, Sushabhan Sadhukhan
Protein S-palmitoylation refers to a post-translational modification (PTM) wherein palmitic acid, a 16-carbon long saturated fatty acid gets covalently attached to Cys sidechain of a protein. It has been known to the literature for almost 50 years and in general, this PTM is believed to facilitate membrane attachments of proteins for the obvious hydrophobicity of the palmitoyl group. But after the discovery of the protein palmitoyl acyltransferases (PATs, also known as DHHC-PATs), a major paradigm shift has been observed in the field of protein S-palmitoylation...
March 22, 2018: European Journal of Cell Biology
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