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Article
| Open AccessGlobal changes of the RNA-bound proteome during the maternal-to-zygotic transition in Drosophila
Early development is controlled by maternally deposited mRNAs and the RNA-binding proteins (RBPs) that regulate them. Here the authors describe the identification of a large number of RBPs bound to polyadenylated RNAs in Drosophilaembryos before and after the maternal-to-zygotic transition, revealing changes in RBPs activity during development.
- Vasiliy O. Sysoev
- , Bernd Fischer
- & Anne Ephrussi
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Article
| Open AccessDistinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses
Abnormal functions of RNA-binding proteins TAF15, FUS and TDP43 are associated with amyotrophic lateral sclerosis. Here, Kapeli et al. characterize the RNA targets of TAF15 and identify points of convergence and divergence between the targets of TAF15, FUS and TDP43 in several neuronal systems.
- Katannya Kapeli
- , Gabriel A. Pratt
- & Gene W. Yeo
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Article
| Open AccessA spliceosome intermediate with loosely associated tri-snRNP accumulates in the absence of Prp28 ATPase activity
The assembly of the splicesome involves several distinct stages that require the sequential action of DExD/H-box RNA helicases. Here, the authors uncover a new intermediate, the pre-B complex, that accumulates in the presence of an inactive form of the DEAD-box protein Prp28.
- Carsten Boesler
- , Norbert Rigo
- & Reinhard Lührmann
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Article
| Open AccessStructure and activation of pro-activin A
Activins are members of the TGF-β family of growth factors that are processed from precursors into the mature proteins. Here, the authors use structural biology and biochemistry to examine the protein domain organisation and gain insights into the activation of pro-activin A.
- Xuelu Wang
- , Gerhard Fischer
- & Marko Hyvönen
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Article
| Open AccessDeficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3
The post-transcriptional 5-methylcytosine (m5C) modification occurs in a wide range of nuclear-encoded RNAs. Here the authors identify the mitochondrial tRNA-Met as a target for the m5C methyltransferase NSun3—found mutated in a mitochondrial disease patient—and link mitochondrial tRNA modifications with energy metabolism.
- Lindsey Van Haute
- , Sabine Dietmann
- & Michal Minczuk
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Article
| Open AccessPironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule
Microtubule assembly and disassembly is the target of many anticancer therapies, with β-tubulin the most-frequent target. Here, the authors used biochemical and biophysical techniques to demonstrate pironetin binds to α-tubulin and thereby inhibits microtubule polymerization providing a basis for the rational design of novel anticancer drugs.
- Jianhong Yang
- , Yuxi Wang
- & Lijuan Chen
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Article
| Open AccessThe FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding
Hsp90 is required for the folding, stability and activity of several drivers of oncogenesis. Here the authors show that Folliculin-interacting proteins (FNIP) 1 and 2, whose expression correlates with the cellular response to Hsp90 inhibitors, are co-chaperones of Hsp90 that function by inhibiting its ATPase activity.
- Mark R. Woodford
- , Diana M. Dunn
- & Mehdi Mollapour
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Article
| Open AccessUtpA and UtpB chaperone nascent pre-ribosomal RNA and U3 snoRNA to initiate eukaryotic ribosome assembly
Eukaryotic ribosome biogenesis involves a large number of maturations factors which are responsible for the stepwise assembly of the ribosomal subunits. Here the authors use an array of biochemical and structural biology methods to investigate the function of the UtpA and UtpB complexes as part of the small subunit processome.
- Mirjam Hunziker
- , Jonas Barandun
- & Sebastian Klinge
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Article
| Open AccessPharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein
Small-molecule chaperones that can prevent protein misfolding have potential applications for treating diseases such as Alzheimer’s and ALS. Here the authors use high-resolution force spectroscopy to gain insight into the mechanism of action of an iron-tetrapyrrole with anti-prion properties.
- Amar Nath Gupta
- , Krishna Neupane
- & Michael T. Woodside
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Article
| Open AccessStructure–function analysis of the extracellular domain of the pneumococcal cell division site positioning protein MapZ
Placement of the bacterial division site is crucial for the creation of identical daughter cells. Here, the authors solve the structure of the MapZ protein, which helps to position the cell division protein FtsZ at the cell centre, and further analyse the function of the protein in vivo.
- Sylvie Manuse
- , Nicolas L. Jean
- & Jean-Pierre Simorre
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Article
| Open AccessPACAP suppresses dry eye signs by stimulating tear secretion
Dry eye disease is a complex condition with limited treatments. Here the authors show that mice lacking a multi-functional peptide PACAP develop dry eye-like signs that can be topically treated with PACAP peptide that stimulates tearing in mice, suggesting a possible therapy in humans with dry eyes.
- Tomoya Nakamachi
- , Hirokazu Ohtaki
- & Seiji Shioda
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Article
| Open AccessCharacterization of the targeting signal in mitochondrial β-barrel proteins
Mitochondrial β-barrel proteins are synthesized in the cytosol before being targeted to the organelle. Here, Jores et al.show that a specialized hydrophobic β-hairpin motif is the previously undefined targeting sequence and is recognized by the mitochondrial outer membrane translocase.
- Tobias Jores
- , Anna Klinger
- & Doron Rapaport
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Article
| Open AccessMapping RNA–RNA interactome and RNA structure in vivo by MARIO
Current methods for mapping RNA-RNA interactions have to rely on an ‘anchor’ protein or RNA. Here, the authors report the MARIO (Mapping RNA interactome in vivo) technology that can massively reveal RNA-RNA interactions and RNA structure from unperturbed cells.
- Tri C. Nguyen
- , Xiaoyi Cao
- & Sheng Zhong
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Article
| Open AccessMYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation
The circadian clock and the cell cycle systems coordinate global physiology. Here the authors show that MYC represses the clock genes, together with MIZ1, and induces proliferation, suggesting that MYC inversely modulates cell cycle and circadian clock genes.
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
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Article
| Open AccessArginine demethylation is catalysed by a subset of JmjC histone lysine demethylases
While reversal of lysine methylation on histone tails is a well-established mechanism to tune gene expression, the existence of a similar arginine demethylation process is controversial. Here, the authors show that some jumonji enzymes possess both lysine and arginine demethylase activity in vitro.
- Louise J. Walport
- , Richard J. Hopkinson
- & Christopher J. Schofield
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Article
| Open AccessActivation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation
Striatal D1 and D2-receptor expressing neurons have been shown to have opposing effects on reward-related behaviours. Here the authors reveal that specific activation of both D1 and D2 neurons in the nucleus accumbens leads to increase in motivational drive in rodents.
- Carina Soares-Cunha
- , Barbara Coimbra
- & Ana J. Rodrigues
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Article
| Open AccessCardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation
Cardiac voltage-gated sodium channels (Nav1.5) are crucial regulators of heart electric activity. Here the authors show that palmitoylation, a process of lipid modification of cysteine residues, modulates Nav1.5 function and affects cardiomyocyte excitability, representing a potential target in treating cardiac diseases.
- Zifan Pei
- , Yucheng Xiao
- & Theodore R. Cummins
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Article
| Open AccessArf6 controls retromer traffic and intracellular cholesterol distribution via a phosphoinositide-based mechanism
The small GTPase Arf6 regulates intracellular transport, phosphoinositide signalling and cholesterol homeostasis. Here, Marquer et al. show that loss of Arf6 causes cholesterol accumulation in endosomes due to defects in phosphoinositide-dependent retromer-mediated trafficking of CI-M6PR and NPC2.
- Catherine Marquer
- , Huasong Tian
- & Gilbert Di Paolo
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Article
| Open AccessStructural basis of suppression of host translation termination by Moloney Murine Leukemia Virus
Retroviral reverse transcriptase from Moloney Murine Leukemia Virus (MoMLV) requires interaction with peptidyl release factor 1. Here, the authors report the crystal structure of this complex, and provide insights into how MoMLV uses the host translation machinery to synthesize its own proteins.
- Xuhua Tang
- , Yiping Zhu
- & Haiwei Song
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Article
| Open AccessThe role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels
The activation of bacterial mechanosensitive channels is still not fully understood. Here, Bavi et al. show that the N-terminal helix of MscL dynamically couples membrane tension to channel gating, suggesting a conserved mechanism underlying the mechanosensitivity of ion channels of higher organisms.
- Navid Bavi
- , D. Marien Cortes
- & Boris Martinac
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Article
| Open AccessStructural basis for the recognition of guide RNA and target DNA heteroduplex by Argonaute
Argonaute proteins are important in the silencing machinery with some regulatory RNAs. Here, the authors solve the structure of an argonaute protein in complex with both the guide RNA and target DNA and propose a mechanism for their recognition.
- Tomohiro Miyoshi
- , Kosuke Ito
- & Toshio Uchiumi
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Article
| Open AccessThe necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance
The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.
- Jérémie Gautheron
- , Mihael Vucur
- & Tom Luedde
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Correspondence
| Open AccessCorrespondence: On the enzymology and significance of HSPA1 lysine methylation
- Magnus E. Jakobsson
- , Anders Moen
- & Pål Ø Falnes
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Article
| Open AccessStructural insights of ZIP4 extracellular domain critical for optimal zinc transport
Mutations in the extracellular domain of zinc transporter ZIP4 result in a lethal disorder. Here, the authors report the first crystal structure of ZIP4 extracellular domain, unveiling its unprecedented dimerization and two structural independent subdomains that have crucial roles in zinc transport.
- Tuo Zhang
- , Dexin Sui
- & Jian Hu
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Article
| Open AccessLoss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice
Mutations in the translational activator of cytochrome c oxidase subunit I (TACO1) causes cytochrome c oxidase deficiency and Leigh Syndrome in patients. Here, the authors characterize mice with a mutation that causes lack of TACO1 expression, identifying a mouse model that could be useful for preclinical trials.
- Tara R. Richman
- , Henrik Spåhr
- & Aleksandra Filipovska
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Article
| Open AccessTranslation control during prolonged mTORC1 inhibition mediated by 4E-BP3
The eIF4E-binding proteins (4E-BPs) are critical repressors of cap-dependent translation via mTOR, a pathway frequently hyperactivated in cancer. Here the authors show that 4E-BP3 specifically mediates the cap-dependent translation repression and antiproliferative effects of prolonged pharmacological mTOR inhibition.
- Yoshinori Tsukumo
- , Tommy Alain
- & Nahum Sonenberg
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Article
| Open AccessA threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
NFATc1 orchestrates thymocyte development. Here the authors show that NFATc1 expression is regulated by distinct promoters during thymocyte differentiation, and by conditional deletion of individual promoters in mice they define their specific roles in the control of T-cell development by NFATc1.
- Stefan Klein-Hessling
- , Ronald Rudolf
- & Amiya Kumar Patra
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Article
| Open AccessStructure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A
Xpo4 imports Sox2 and other proteins into the cell nucleus, while exporting eIF5A or Smad3; how it recognizes these proteins has been unclear. Here, the authors solved the crystal structure of the RanGTP, Xpo4 and eIF5A complex and investigate how Xpo4 identifies its major export cargo.
- Metin Aksu
- , Sergei Trakhanov
- & Dirk Görlich
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Article
| Open AccessDirect evidence of the molecular basis for biological silicon transport
Diatoms sheath themselves in a self-made casing of silica, which requires the function of silicic acid transporters. Here, the authors identify versions of these transporters that are experimentally tractable, and develop a fluorescence method to study silicic acid transport in vitro.
- Michael J. Knight
- , Laura Senior
- & Paul Curnow
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Article
| Open AccessSuspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells
Tumour initiating cells (TICs) are anoikis resistant in suspension culture and they are critical for initiating tumorigenesis in vivo. Here, the authors show that these features are promoted by hemidesmosome-like structures enriched in laminin V and collagen XVII 5 upregulated in TICs by phospho-STAT3 whose levels are increased through PP2A inactivation.
- Chen-Chi Liu
- , Shih-Pei Lin
- & Shih-Chieh Hung
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Article
| Open AccessGenome editing in butterflies reveals that spalt promotes and Distal-less represses eyespot colour patterns
Transcription factors Distal-less(Dll) and spalt were co-opted during the evolution of butterfly eyespots. Here, Zhang and Reed use CRISPR/Cas9 genome editing to show that while spalt is a positive regulator of eyespots as predicted, Dll knockouts have positive effects on both eyespot size and number, thus suggesting that Dllis an eyespot repressor, not an activator as previously thought.
- Linlin Zhang
- & Robert D. Reed
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Article
| Open AccessA CD36 ectodomain mediates insect pheromone detection via a putative tunnelling mechanism
The CD36-related Sensory Neuron Membrane Protein 1 (SNMP1) facilitates pheromone detection by insect odorant receptors. Here Gomez-Diaz et al.show that the SNMP1 ectodomain is essential for function and propose that it forms a tunnel that transports pheromones from the extracellular fluid to their cognate receptors.
- Carolina Gomez-Diaz
- , Benoîte Bargeton
- & Richard Benton
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Article
| Open AccessCalredoxin represents a novel type of calcium-dependent sensor-responder connected to redox regulation in the chloroplast
Calcium and redox signalling have important roles in acclimation processes. Here, the authors characterise a protein from Chlamydomonas reinhardtiithat can integrate calcium and redox-related signalling.
- Ana Karina Hochmal
- , Karen Zinzius
- & Michael Hippler
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Article
| Open AccessInterphase adhesion geometry is transmitted to an internal regulator for spindle orientation via caveolin-1
Studies imply that cell adhesion geometry during interphase dictates the orientation of the cell division axis. Here the authors show that accumulation of caveolin-1 to rapidly retracting regions during cell rounding sets the spindle orientation by recruiting Gαi1-LGN-NuMA to the cortex.
- Shigeru Matsumura
- , Tomoko Kojidani
- & Fumiko Toyoshima
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Article
| Open AccessVisualizing the formation of an RNA folding intermediate through a fast highly modular secondary structure switch
Short-lived RNA folding intermediates have important roles in the folding of RNA. Here, the authors combine 15N relaxation dispersion NMR with chemical probing to visualise one of these intermediates, and are able to show it is a secondary structural switch, that might help with folding.
- Yi Xue
- , Brant Gracia
- & Hashim M. Al-Hashimi
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Article
| Open AccessLong noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation
Long noncoding RNAs have a wide range of physiological functions, though their role in viral infection and latency is poorly understood. Here the authors show a lncRNA NRON can induce degradation of HIV-1 protein Tat, potentially contributing to latent infection.
- Jun Li
- , Cancan Chen
- & Hui Zhang
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Article
| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang
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Article
| Open AccessMTHFD1 controls DNA methylation in Arabidopsis
DNA methylation contributes to transcriptional silencing. Here, Groth et al.show that mutant plants defective in MTHFD1, an enzyme involved in folate metabolism, have a DNA hypomethylation phenotype highlighting the link between one-carbon metabolism and DNA methylation, which is mediated by SAM as a common methyl donor.
- Martin Groth
- , Guillaume Moissiard
- & Steven E. Jacobsen
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Article
| Open AccessCrystal structure of NOD2 and its implications in human disease
NOD2 has a role in host innate immune responses, activating the NF-κB signalling pathway and mutations have been associated with chronic inflammatory disorders. Here, Maekawa et al. solved the structure of NOD2 in its inactive form, suggesting a mechanism for autoinhibition.
- Sakiko Maekawa
- , Umeharu Ohto
- & Toshiyuki Shimizu
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Article
| Open AccessGolgi-localized STELLO proteins regulate the assembly and trafficking of cellulose synthase complexes in Arabidopsis
Cellulose is produced in plants by cellulose synthase complexes (CSCs) that are assembled in the endomembrane system and then trafficked to the plasma membrane. Here Zhang et al. show that the Golgi-localized STELLO1 and 2 proteins are required for the proper assembly and distribution of CSCs in plant cells.
- Yi Zhang
- , Nino Nikolovski
- & Paul Dupree
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Article
| Open AccessThe Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway
Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson’s disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.
- Carla F. Bento
- , Avraham Ashkenazi
- & David C. Rubinsztein
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Article
| Open AccessSyndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD
Syndecans are transmembrane proteoglycans implicated in diverse cellular activities. Here the authors show that Syndecan-4 via its cytosolic domain negatively regulates antiviral immunity by enhancing RIG-I interaction with a deubiquitinating enzyme CYLD, thus inhibiting the activating K63-linked RIG-I ubiquitination.
- Wei Lin
- , Jing Zhang
- & Qinmiao Sun
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Article
| Open AccessMitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification
Plant cells maintain strict proton gradients over different membranes. Here, Dejonghe et al. show that several protonophores, including the known tyrosine kinase inhibitor TyrphostinA23, inhibit clathrin-mediated endocytosis by disturbing these gradients and causing cytoplasmic acidification.
- Wim Dejonghe
- , Sabine Kuenen
- & Eugenia Russinova
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Article
| Open AccessGPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis
GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Here the authors report that GPRC5A suppresses the translation of EGFR by interfering with the eIF4F complex assembly, thereby limiting lung tumorigenesis, particularly radiation-induced lung tumorigenesis.
- Jian Wang
- , Alton B. Farris
- & Ya Wang
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Article
| Open AccessThe T300A Crohn’s disease risk polymorphism impairs function of the WD40 domain of ATG16L1
The T300A substitution in ATG16L is associated with Crohn’s disease risk and disrupts clearance of intracellular pathogens by autophagy. Here the authors show that the mutation impairs interaction of ATG16L with TMEM59 and disrupts unconventional TMEM-induced autophagy, an aspect of innate immunity.
- Emilio Boada-Romero
- , Inmaculada Serramito-Gómez
- & Felipe X. Pimentel-Muiños
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Article
| Open AccessA replicator-specific binding protein essential for site-specific initiation of DNA replication in mammalian cells
Origins of mammalian DNA replication are poorly characterised because they lack an Identifiable consensus sequence. Here the authors identify RepID, a protein that binds to a subset of G-rich replication origins and facilitates initiation from those origins.
- Ya Zhang
- , Liang Huang
- & Mirit I. Aladjem
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Article
| Open AccessUbiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1
Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.
- Frederick C. Nucifora Jr
- , Leslie G. Nucifora
- & Christopher A. Ross
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Article
| Open AccessThe Arabidopsis acetylated histone-binding protein BRAT1 forms a complex with BRP1 and prevents transcriptional silencing
Transposons and repetitive sequences are typically subject to transcription silencing. Here, Zhang et al. find that the bromodomain-containing protein BRAT1 forms a complex with BRP1, recognizes histone acetylation and acts to prevent transcriptional silencing in Arabidopsis.
- Cui-Jun Zhang
- , Xiao-Mei Hou
- & Xin-Jian He
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Article
| Open AccessUnravelling the structural plasticity of stretched DNA under torsional constraint
Cellular DNA is often torsionally constrained, but the topologies that such DNA can adopt under tensile strain have remained largely untested. Here, the authors use single-molecule optical tweezers to illustrate the structural plasticity of torsionally constrained DNA under mechanical force.
- Graeme A. King
- , Erwin J. G. Peterman
- & Gijs J. L. Wuite
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