5823 Widewaters Pkwy
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Type II Turn of Receptor-bound Salmon Calcitonin Revealed by X-ray Crystallography. - The Journal of biological chemistry
Calcitonin is a peptide hormone consisting of 32 amino acid residues and the calcitonin receptor is a Class B G protein-coupled receptor (GPCR). The crystal structure of the human calcitonin receptor ectodomain (CTR ECD) in complex with a truncated analogue of salmon calcitonin ([BrPhe22]sCT(8-32)) has been determined to 2.1 Ã… resolution. Parallel analysis of a series of peptide ligands showed that the rank order of binding of the CTR ECD is identical to the rank order of binding of the full length CTR, confirming the structural integrity and relevance of the isolated CTR ECD. The structure of the CTR ECD is similar to other Class B GPCRs and the ligand binding site is similar to the binding site of the homologous receptors for the calcitonin gene-related peptide (CGRP) and adrenomedulin (AM) recently published. Interestingly the receptor-bound structure of the ligand [BrPhe22]sCT(8-32) differs from the receptor-bound structure of the homologous ligands CGRP and AM. They all adopt an extended conformation followed by a carboxy terminal beta turn, however, [BrPhe22]sCT(8-32) adopts a type II turn (Gly28-Thr31) whereas CGRP and AM adopt type I turns. Our results suggest that a type II turn is the preferred conformation of calcitonin whereas a type I turn is the preferred conformation of peptides that require receptor activity-modifying proteins (RAMPs); CGRP, AM and amylin. In addition the structure provides a detailed molecular explanation and hypothesis regarding ligand binding properties of CTR and the amylin receptors.Copyright Â© 2016, The American Society for Biochemistry and Molecular Biology.
Combinatorial Histone Acetylation Patterns Are Generated by Motif-Specific Reactions. - Cell systems
Post-translational modifications (PTMs) are pivotal to cellular information processing, but how combinatorial PTM patterns ("motifs") are set remains elusive. We develop a computational framework, which we provide as open source code, to investigate the design principles generating the combinatorial acetylation patterns on histone H4 in Drosophila melanogaster. We find that models assuming purely unspecific or lysine site-specific acetylation rates were insufficient to explain the experimentally determined motif abundances. Rather, these abundances were best described by an ensemble of models with acetylation rates that were specific to motifs. The model ensemble converged upon four acetylation pathways; we validated three of these using independent data from a systematic enzyme depletion study. Our findings suggest that histone acetylation patterns originate through specific pathways involving motif-specific acetylation activity.Copyright Â© 2016 Elsevier Inc. All rights reserved.
High levels of histone H3 acetylation at the CMV promoter are predictive of stable expression in Chinese Hamster Ovary cells. - Biotechnology progress
Chinese hamster ovary cells (CHO) are widely used in the production of glycosylated therapeutic proteins such as antibodies. During expansion and maintenance, CHO cell lines are prone to production instability, which may be caused by promoter silencing, loss of transgene copies, or post-transcriptional effects. Silencing of recombinant genes may be accompanied by DNA methylation and histone modification. Previously, we demonstrated that cytosine methylation of the human cytomegalovirus major immediate early promoter/enhancer (hCMV-MIE) can be used to predict instability of antibody-producing CHO cell lines. However, the high rate of false prediction motivates the search for further markers of stable promoter activity. To this end, we correlated a variety of histone modifications in the vicinity of hCMV-MIE with production stability over time. Our results suggest that acetylation of histone H3 (H3ac) is a more effective indicator of production stability than DNA methylation. Selecting cell lines with highest CMV promoter H3ac levels enriches stable expressors and improves the average stability of production cell lines. For histone H3 acetylation measurement we employed a method based on chromatin immunoprecipitation (ChIP). In its current form, the method is suitable to evaluate 10 to 20 cell lines within a few days. We propose to determine H3 acetylation once the number of candidate cell lines has been narrowed based on productivity and product quality. This article is protected by copyright. All rights reserved.Â© 2016 American Institute of Chemical Engineers.
Mechanochemical Iridium(III)-Catalyzed C-H Bond Amidation of Benzamides with Sulfonyl Azides under Solvent-Free Conditions in a Ball Mill. - Angewandte Chemie (International ed. in English)
Mechanochemical conditions have been applied to an iridium(III)-catalyzed C-H bond amidation process for the first time. In the absence of solvent, the mechanochemical activation enables the formation of an iridium species that catalyzes the ortho-selective amidation of benzamides with sulfonyl azides as the nitrogen source. As the reaction proceeds in the absence of organic solvents without external heating and yields the desired products in excellent yields within short reaction times, this method constitutes a powerful, fast, and environmentally benign alternative to the common solvent-based standard approaches.Â© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
A role for tuned levels of nucleosome remodeler subunit ACF1 during Drosophila oogenesis. - Developmental biology
The Chromatin Accessibility Complex (CHRAC) consists of the ATPase ISWI, the large ACF1 subunit and a pair of small histone-like proteins, CHRAC-14/16. CHRAC is a prototypical nucleosome sliding factor that mobilizes nucleosomes to improve the regularity and integrity of the chromatin fiber. This may facilitate the formation of repressive chromatin. Expression of the signature subunit ACF1 is restricted during embryonic development, but remains high in primordial germ cells. Therefore, we explored roles for ACF1 during Drosophila oogenesis. ACF1 is expressed in somatic and germline cells, with notable enrichment in germline stem cells and oocytes. The asymmetrical localization of ACF1 to these cells depends on the transport of the Acf1 mRNA by the Bicaudal-D/Egalitarian complex. Loss of ACF1 function in the novel Acf1(7) allele leads to defective egg chambers and their elimination through apoptosis. In addition, we find a variety of unusual 16-cell cyst packaging phenotypes in the previously known Acf1(1) allele, with a striking prevalence of egg chambers with two functional oocytes at opposite poles. Surprisingly, we found that the Acf1(1) deletion - despite disruption of the Acf1 reading frame - expresses low levels of a PHD-bromodomain module from the C-terminus of ACF1 that becomes enriched in oocytes. Expression of this module from the Acf1 genomic locus leads to packaging defects in the absence of functional ACF1, suggesting competitive interactions with unknown target molecules. Remarkably, a two-fold overexpression of CHRAC (ACF1 and CHRAC-16) leads to increased apoptosis and packaging defects. Evidently, finely tuned CHRAC levels are required for proper oogenesis.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. - EMBO reports
Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl-CoA levels, alterations in protein-notably histone-acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12-specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.Â© 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
CMV promoter mutants with a reduced propensity to productivity loss in CHO cells. - Scientific reports
The major immediate-early promoter and enhancer of the human cytomegalovirus (hCMV-MIE) is one of the most potent DNA elements driving recombinant gene expression in mammalian cells. Therefore, it is widely employed not only in research but also in large-scale industrial applications, e.g. for the production of therapeutic antibodies in Chinese hamster ovary cells (CHO). As we have reported previously, multi-site methylation of hCMV-MIE is linked to productivity loss in permanently transfected CHO cells lines. In particular, the cytosine located 179â€‰bp upstream of the transcription start site (C-179) is frequently methylated. Therefore, our objective was to study whether mutation of C-179 and other cytosines within hCMV-MIE might lessen the instability of transgene expression. We discovered that the single mutation of C-179 to G can significantly stabilise the production of recombinant protein under control of hCMV-MIE in permanently transfected CHO cells.
Structure of the RNA Helicase MLE Reveals the Molecular Mechanisms for Uridine Specificity and RNA-ATP Coupling. - Molecular cell
The MLE helicase remodels the roX lncRNAs, enabling the lncRNA-mediated assembly of the Drosophila dosage compensation complex. We identified a stable MLE core comprising the DExH helicase module and two auxiliary domains: a dsRBD and an OB-like fold. MLEcore is an unusual DExH helicase that can unwind blunt-ended RNA duplexes and has specificity for uridine nucleotides. We determined the 2.1Â Ã… resolution structure of MLEcore bound to a U10 RNA and ADP-AlF4. The OB-like and dsRBD folds bind the DExH module and contribute to form the entrance of the helicase channel. Four uridine nucleotides engage in base-specific interactions, rationalizing the conservation of uridine-rich sequences in critical roX substrates. roX2 binding is orchestrated by MLE's auxiliary domains, which is prerequisite for MLE localization to the male X chromosome. The structure visualizes a transition-state mimic of the reaction and suggests how eukaryotic DEAH/RHA helicases couple ATP hydrolysis to RNA translocation.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Acylsilanes in Iridium-Catalyzed Directed Amidation Reactions and Formation of Heterocycles via Siloxycarbenes. - Angewandte Chemie (International ed. in English)
Exposing ortho-amido aroylsilanes to visible light or heat leads to cyclization reactions that provide N-heterocyclic compounds via siloxycarbenes as key intermediates. The previously unreported starting materials have been prepared by directed amidations of aromatic acylsilanes in the presence of an iridium catalyst followed by N-alkylation.Â© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Archiving Primary Data: Solutions for Long-Term Studies. - Trends in ecology & evolution
The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern. We present here their viewpoint on an issue that can have non-trivial scientific consequences. We discuss potential costs of public data archiving and provide possible solutions to meet the needs of journals and researchers.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
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