Nature Chemical Biology Contents: November 2014 Volume 10 No 11 pp 869 - 983

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TABLE OF CONTENTS November 2014 Volume 10, Issue 11 Focus Editorial Commentary Elements Research Highlights News and Views Perspective Reviews Brief Communications Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement A picture of health  Reporter Lorna Stewart travels to the German island of Lindau to meet 600 of science’s brightest young minds and 37 rock stars – Nobel laureates. In a series of four films, Stewart asks some of the most profound questions in medicine.   Watch the videos online.   Published weekly from 24th Sep- 15th Oct 2014    Supported by Mars, Incorporated     Focus Top Proteostasis Proteostasis is a cellular network that ensures proteome integrity. In this focus issue, we present a collection of articles that discuss how recent advances in chemical biology are improving our mechanistic understanding of proteostasis and are guiding the development of chemical tools and small molecules to probe protein homeostasis. Proteostasis Editorial Top First aid for a damaged proteome   p869 doi:10.1038/nchembio.1684 New insights into the regulatory mechanisms of protein folding and turnover are informing the development of chemical tools and small molecules to treat proteostasis disorders. Commentary Top Sculpting the proteome with small molecules   pp870 - 874 Randall W King and Daniel Finley doi:10.1038/nchembio.1671 The ubiquitin-proteasome system (UPS) pervades the biology of eukaryotes. Because it depends on the activity of hundreds of different enzymes and protein-protein interactions, the UPS provides many opportunities for selective modulation of the pathway with small molecules. Here we discuss the principles that underlie the development of effective inhibitors or activators of the pathway. We emphasize insights from structural analysis and describe strategies for evaluating the selectivity of compounds. Elements Top Rick Morimoto   p875 Catherine Goodman doi:10.1038/nchembio.1682 A pioneer in proteostasis is changing the way we think about organismal biology and human disease. Research Highlights Top Alzheimer's disease: Making A[beta] better | Chemical tools: Pass the persulfides | Post-translational modifications: SUMO size me | Cell cycle: Mitotic tag team | Unfolded protein response: Letting go of stress | Carbohydrates: Cutting out starch | Target identification: NAD salvages neurons | Protein turnover: Mitochondrial immaturity News and Views Top Enzymology: A radical finding   pp878 - 879 Rebecca J M Goss and Sabine Gruschow doi:10.1038/nchembio.1649 A new family of radical halogenases has been discovered that regio- and stereoselectively chlorinates the unactivated carbon center of indolemonoterpenoid substrates without the prerequisite for the substrate to be bound to a protein carrier. See also: Brief Communication by Hillwig & Liu Protein homeostasis: Modeling UPR adaptive responses   pp879 - 880 Danilo B Medinas and Claudio Hetz doi:10.1038/nchembio.1653 Understanding the mechanisms that determine cell fate under endoplasmic reticulum (ER) stress had been hampered by the lack of models to study unfolded protein response (UPR) adaptive phases. The development of an engineered protein to conditionally induce its misfolding allowed the establishment of a resolvable ER stress condition. See also: Article by Raina et al. Protein trafficking: RESETting proteostasis   pp881 - 882 Julia Noack and Maurizio Molinari doi:10.1038/nchembio.1652 A recent study reveals a new cellular pathway that clears the endoplasmic reticulum of misfolded, GPI-anchored proteins at the onset of endoplasmic reticulum (ER) stress. This mechanism, termed rapid ER stress-induced export, represents a nontranscriptional response to mitigate acute ER stress. Vaccine development: NKT-cell adjuvants in conjugate   pp882 - 883 Paul B Savage doi:10.1038/nchembio.1667 Two studies demonstrate that natural killer T-cell adjuvants, covalently attached to either carbohydrate or peptide epitopes, yield effective vaccines. See also: Article by Anderson et al. | Article by Cavallari et al. Chemical Biology JOBS of the week Faculty Positions Available at the State Key Laboratory of Medicinal Chemical Biology (Nankai University) Nankai University PhD Studentship in NMR Spectroscopy and Chemical Biology University of Auckland Postdoctoral Research Associate University of Wisconsin School of Medicine and Public Health Postdoctoral position in Single-Cell Biology of the Nucleus Karolinska Institutet (KI) Tier 2 Canada Research Chair in Systems Biology University of Ottawa More Science jobs from Chemical Biology EVENT Advances & Progress in Drug Design 16 February 2015 London, UK More science events from Perspective Top Energy landscapes of functional proteins are inherently risky   pp884 - 891 Anne Gershenson, Lila M Gierasch, Annalisa Pastore and Sheena E Radford doi:10.1038/nchembio.1670 Reviews Top Druggable sensors of the unfolded protein response   pp892 - 901 Dustin J Maly and Feroz R Papa doi:10.1038/nchembio.1664 The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis   pp902 - 910 Daniel N Hebert, Lydia Lamriben, Evan T Powers and Jeffery W Kelly doi:10.1038/nchembio.1651 Combating neurodegenerative disease with chemical probes and model systems   pp911 - 920 Priyanka Narayan, Sepehr Ehsani and Susan Lindquist doi:10.1038/nchembio.1663 Brief Communications Top A new family of iron-dependent halogenases acts on freestanding substrates   pp921 - 923 Matthew L Hillwig and Xinyu Liu doi:10.1038/nchembio.1625 Nonheme iron halogenases, or enzymes that perform oxidative halogenations, exist in a variety of biosynthetic pathways and modify substrates attached to carrier proteins. Biochemical evidence defines a chlorinase that breaks this rule, acting on soluble substrates. See also: News and Views by Goss & Gruschow Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis   pp924 - 926 Ravshan Burikhanov, Vitaliy M Sviripa, Nikhil Hebbar, Wen Zhang, W John Layton et al. doi:10.1038/nchembio.1631 Arylquin 1 was identified as a Par-4 secretagogue that binds the cytoskeletal intermediate filament protein vimentin and disrupts Par-4–vimentin interactions. The release of Par-4 promotes the apoptosis of cancer cells. Chemical compounds Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain   pp927 - 929 Chao Xu, Xiao Wang, Ke Liu, Ian A Roundtree, Wolfram Tempel et al. doi:10.1038/nchembio.1654 N6-methyladenosine (m6A) is an abundant eukaryotic RNA modification that regulates mRNA stability. Biochemical analysis and crystallographic visualization of m6A-YTHDC1 interactions establish this YTH family member as an m6A reader and explain its RNA consensus sequence selectivity. Articles Top Chemomechanical coupling of human mitochondrial F1-ATPase motor   pp930 - 936 Toshiharu Suzuki, Kazumi Tanaka, Chiaki Wakabayashi, Ei-ichiro Saita and Masasuke Yoshida doi:10.1038/nchembio.1635 A single-molecule study of the dwell times and other features along the full rotation for the human mitochondrial F1-ATPase positions the catalytic events (ATP binding, Pi release and ATP hydrolysis) and reveals differences from the bacterial system. Substrate-dependent switching of the allosteric binding mechanism of a dimeric enzyme   pp937 - 942 Lee Freiburger, Teresa Miletti, Siqi Zhu, Oliver Baettig, Albert Berghuis et al. doi:10.1038/nchembio.1626 Structural and biochemical studies of an acetyltransferase demonstrate that conformational changes differ depending on the ligand bound, indicating that binding cooperativity is more complex than expected. A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy   pp943 - 949 Regan J Anderson, Ching-wen Tang, Naomi J Daniels, Benjamin J Compton, Colin M Hayman et al. doi:10.1038/nchembio.1640 A vaccine combining an allergen-specific CD8+ T-cell epitope with an invariant natural killer T (iNKT) cell agonist stimulates immune responses in an animal model of asthma. Rather than a typical pattern recognition receptor ligand as adjuvant, the iNKT agonist used was a glycolipid. Chemical compounds See also: News and Views by Savage | Article by Cavallari et al. A semisynthetic carbohydrate-lipid vaccine that protects against S. pneumoniae in mice   pp950 - 956 Marco Cavallari, Pierre Stallforth, Artem Kalinichenko, Dominea C K Rathwell, Thomas M A Gronewold et al. doi:10.1038/nchembio.1650 A semisynthetic carbohydrate-lipid vaccine that combines a known adjuvant that has been used in disease models with a lipid capable of activating iNKT cells protects against Streptococcus pneumoniae infection in mice. See also: News and Views by Savage | Article by Anderson et al. Targeted protein destabilization reveals an estrogen-mediated ER stress response   pp957 - 962 Kanak Raina, Devin J Noblin, Yevgeniy V Serebrenik, Alison Adams, Connie Zhao et al. doi:10.1038/nchembio.1638 The use of an endoplasmic reticulum–localized HaloTag system results in protein destabilization and activation of a transient unfolding protein response (UPR) without causing cell death, allowing the examination of later stage UPR events. See also: News and Views by Medinas & Hetz A roadmap for natural product discovery based on large-scale genomics and metabolomics   pp963 - 968 James R Doroghazi, Jessica C Albright, Anthony W Goering, Kou-San Ju, Robert R Haines et al. doi:10.1038/nchembio.1659 A global bioinformatic classification of >11,000 biosynthetic gene clusters from >800 bacterial genomes and cross-correlation with metabolomics data from nearly 200 strains sets the stage for targeted natural product discovery. Unraveling the mechanism of cell death induced by chemical fibrils   pp969 - 976 Olivier Julien, Martin Kampmann, Michael C Bassik, Julie A Zorn, Vincent J Venditto et al. doi:10.1038/nchembio.1639 A small-molecule activator of procaspase 3, 1541, forms chemical fibrils. shRNA screens, caspase proteomics and small-molecule profiling reveal that these fibrils enter cells through endocytosis and promote a distinctive form of cell death. An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis   pp977 - 983 Mihalis S Kariolis, Yu Rebecca Miao, Douglas S Jones II, Shiven Kapur, Irimpan I Mathews et al. doi:10.1038/nchembio.1636 Protein engineering strategies introduced mutations into the Axl receptor, which bind and trap the Gas6 ligand with high affinity, preventing the activation of downstream signaling pathways. Top Advertisement Nature has once again been ranked the N0.1 weekly science journal with an Impact Factor of 42.351*. Subscribe to Nature for only $42, £42 or €42. You will receive print, online and app access, providing unbelievable value for money. This is a limited time offer - so don't miss out and subscribe today!   *2013 Journal Citation Reports® (Thomson Reuters, 2014)   Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. 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