Featured
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| Open AccessUniversal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein
There is a lack of vaccines for prevention of human respirovirus 3 (RV3) infection. Bakkers et al. report the design of a stabilized RV3 preF protein vaccine candidate that induces strong neutralizing antibodies and protective responses in small animal models.
- Johannes P. M. Langedijk
- , Freek Cox
- & Mark J. G. Bakkers
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Article
| Open AccessThe debranching enzyme Dbr1 regulates lariat turnover and intron splicing
Dbr1 exhibits debranching specificity and effect on splicing. Here the authors combine co-immunoprecipitation, RNA binding and lariat analysis and suggest a role for Dbr1 interactor AQR in intron recycling. Dbr1 depletion leads to increased dwell time of spliceosome on excised lariats.
- Luke Buerer
- , Nathaniel E. Clark
- & William G. Fairbrother
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Article
| Open AccessStructures of co-transcriptional RNA capping enzymes on paused transcription complex
5′-end capping of pre-mRNA is tightly coupled with the pausing stage of transcription. Here, the authors determine the cryo-EM structures of the paused elongation complex in complex with RNGTT and with both RNGTT and CMTR1.
- Yan Li
- , Qianmin Wang
- & Ze Li
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Article
| Open AccessStructural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease
Human HtrA2 plays an important part in the cellular protein quality control system. Here, advanced NMR spectroscopy unravels the initial activation steps of HtrA2 upon activating peptide binding and the mechanistic role of divalent cations.
- Emelie E. Aspholm
- , Jens Lidman
- & Björn M. Burmann
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Article
| Open AccessStructural basis for selectivity and antagonism in extracellular GPCR-nanobodies
Nanobodies are promising GPCR-targeting therapeutics. Here, the authors investigate a nanobody targeting atypical chemokine receptor 3 (ACKR3), and map trends in GPCR nanobody structure, mechanism, and selectivity.
- Roman R. Schlimgen
- , Francis C. Peterson
- & Brian F. Volkman
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Article
| Open AccessCryo-EM structures of Thogoto virus polymerase reveal unique RNA transcription and replication mechanisms among orthomyxoviruses
In this study the authors present the Thogoto virus polymerase cryo-EM structures and reveal unique RNA synthesis mechanisms among orthomyxoviruses. RNA synthesis by Thogoto virus polymerase is shown to be weakly dependent on the host factors ANP32A/B/E in human cells in contrast to influenza viruses.
- Lu Xue
- , Tiancai Chang
- & Xiaoli Xiong
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Article
| Open AccessTCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks
Replication stress induces STING-TRPV2 dissociation to promote Ca2+ release from the ER for fork protection; however, the precise mechanism remains unclear. Here, the authors identify TCAF1 as a fork protection factor that facilitates STING-TRPV2 dissociation, thereby enabling Ca2+ release.
- Lingzhen Kong
- , Chen Cheng
- & Zhongsheng You
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Article
| Open AccessInflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels
Inflammation promotes insulin resistance in adipocytes, but the mechanism is unclear. Here, the authors show that the inflammatory transcription factor IRF3 drives expression of AIG1, which encodes a hydrolase that breaks down a class of insulin-sensitizing lipid called FAHFAs.
- Shuai Yan
- , Anna Santoro
- & Evan D. Rosen
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Article
| Open AccessFunctional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines
The study identified and structurally characterized the UDP-glycosyltransferases (UGTs) responsible for regioselective glycosylation of wolfberry-derived bioactive lycibarbarspermidines, elucidating the molecular basis for their substrate specificity.
- Shao-Yang Li
- , Gao-Qian Wang
- & Hao Gao
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Article
| Open AccessBinding of Akkermansia muciniphila to mucin is O-glycan specific
Intestinal mucus consists of densely O-glycosylated mucins, serving as a nutrient source for bacteria. Elzinga et al. show that mucin-degrading Akkermansia muciniphila selectively binds to O-glycan structures found on human colonic mucins.
- Janneke Elzinga
- , Yoshiki Narimatsu
- & Hanne L. P. Tytgat
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Article
| Open AccessG protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
Here authors aim to understand the 5-HT2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.
- Elk Kossatz
- , Rebeca Diez-Alarcia
- & Jana Selent
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Article
| Open AccessSmall molecule induced STING degradation facilitated by the HECT ligase HERC4
In this paper, Mutlu et al. identifies a STING degrader, AK59, which inhibits downstream cGAS/STING activity through STING degradation employing a HECT-domain E3 ligase HERC4 and proteasomal ubiquitination pathway.
- Merve Mutlu
- , Isabel Schmidt
- & Danilo Guerini
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Article
| Open AccessGut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction
Here, in a follow-up of a clinical study, the authors show that protein pacing and intermittent fasting improves gut symptomatology and microbial diversity, as well as reduces visceral fat compared to a heart-healthy, calorie-restricted diet matched for overall energy intake and expenditure in free-living humans.
- Alex E. Mohr
- , Karen L. Sweazea
- & Paul J. Arciero
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Article
| Open AccessDynamics underlie the drug recognition mechanism by the efflux transporter EmrE
Here, the authors reveal the protonation of a single membrane embedded glutamate residue within the homodimer of the efflux transporter EmrE modulates the structure and dynamics in an allosteric manner using NMR spectroscopy.
- Jianping Li
- , Ampon Sae Her
- & Nathaniel J. Traaseth
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Article
| Open AccessNucleosomal DNA has topological memory
Here, the authors develop Topo-seq to measure the DNA topology (∆Lk) restrained by individual nucleosomes in vivo. They show that nucleosome DNA topology is imprinted by its native chromatin context and persists when the nucleosome is relocated.
- Joana Segura
- , Ofelia Díaz-Ingelmo
- & Joaquim Roca
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Article
| Open AccessControl of artificial membrane fusion in physiological ionic solutions beyond the limits of electroformation
Membrane fusion is crucial for fabricating artificial membranes. Here, the authors present an approach combining electric field with hydraulic pressure to physically control the fusion, enabling tuning of the shape and size of the 3D freestanding lipid bilayers in physiological solutions.
- Bong Kyu Kim
- , Dong-Hyun Kang
- & Tae Song Kim
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Article
| Open AccessRegiodivergent biosynthesis of bridged bicyclononanes
Hypericum plants contain complex compounds with promising medicinal properties. Here, the authors report a pair of enzymes catalyzing prenylation and regiodivergent cyclization. The forged scaffolds are characteristic of hyperforin analogs.
- Lukas Ernst
- , Hui Lyu
- & Benye Liu
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Article
| Open AccessHairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Lipid droplet (LD) function relies on protein partitioning between the endoplasmic reticulum (ER) and LD. The authors show that UBXD8 adopts distinct conformations in both membranes and undergoes structural rearrangements during ER-to-LD partitioning.
- Ravi Dhiman
- , Rehani S. Perera
- & Bianca Schrul
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Article
| Open AccessProton-coupled transport mechanism of the efflux pump NorA
Efflux pumps confer antibiotic resistance by coupling proton import with drug export. In this work, the authors uncover the proton-coupled transport mechanism for the clinically relevant efflux pump NorA from the pathogenic bacterium S. aureus.
- Jianping Li
- , Yan Li
- & Nathaniel J. Traaseth
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Article
| Open AccessApo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform
Incomplete proteolysis of amyloid-β (Aβ) peptides by γ-secretases is linked to Alzheimer’s disease. Using cryo-EM and functional analyses, this study uncovers the γ-secretase – Aβ46 structure and unveils key interactions for efficient Aβ cleavage.
- Ivica Odorčić
- , Mohamed Belal Hamed
- & Rouslan G. Efremov
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Article
| Open AccessSpa2 remodels ADP-actin via molecular condensation under glucose starvation
Here the authors show that Spa2 orchestrates adaptive actin remodelling in budding yeast by dynamically binding ADP-actin and inducing phase separation on F-actin, a crucial response to energy starvation.
- Qianqian Ma
- , Wahyu Surya
- & Yansong Miao
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Article
| Open AccessHuman neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head
Here the authors isolate two human antibodies, H7.HK1 and H7.HK2, that achieve broad and potent neutralization against H7N9 influenza by targeting a distinct lateral patch on the hemagglutinin head, thus making them favorable to complement other antibodies for combination therapy.
- Manxue Jia
- , Hanjun Zhao
- & Xueling Wu
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Article
| Open AccessProteomic analysis of the urothelial cancer landscape
Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.
- Franz F. Dressler
- , Falk Diedrichs
- & Ákos Végvári
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Article
| Open AccessRab30 facilitates lipid homeostasis during fasting
Despite the importance of Rab GTPases in maintaining the integrity of vesicle trafficking, their physiological roles are not well understood. Here, the authors define a role for Rab30 in supporting lipid homeostasis during fasting in the mouse.
- Danielle M. Smith
- , Brian Y. Liu
- & Michael J. Wolfgang
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Article
| Open AccessContractile injection systems facilitate sporogenic differentiation of Streptomyces davawensis through the action of a phage tapemeasure protein-related effector
Bacteria can use contractile injection systems, similar to viral tail structures, to deliver toxic proteins into other cells. Here, Nagakubo et al. identify a related system that modulates sporulation in multicellular Streptomyces bacteria.
- Toshiki Nagakubo
- , Tatsuya Nishiyama
- & Masanori Toyofuku
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Article
| Open AccessUltrafast energy quenching mechanism of LHCSR3-dependent photoprotection in Chlamydomonas
The Light Harvesting Complex Stress-Related Protein (LHCSR) can protect algae from severe photodamage via energy-dependent quenching (qE). Here, the authors find that a photoproduct of carotenoid S1 state is populated in qE and depopulated in 7.5 ps.
- Mengyuan Zheng
- , Xiaojie Pang
- & Lijin Tian
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Article
| Open AccessBiochemical-free enrichment or depletion of RNA classes in real-time during direct RNA sequencing with RISER
It is difficult to detect low abundance RNAs in sequencing experiments, and biochemical methods to enrich or deplete specific RNAs are time-consuming, costly and can damage RNA. Here, authors develop a biochemical-free technology to enrich or deplete RNA classes in real-time during direct RNA sequencing.
- Alexandra Sneddon
- , Agin Ravindran
- & Eduardo Eyras
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Article
| Open AccessImpact of secretin receptor homo-dimerization on natural ligand binding
GPCRs can form functionally important dimers. Here, authors study impact of dimerization of the secretin receptor on peptide ligand binding and show high receptor conformational dynamics that facilitate G protein recruitment and activation.
- Kaleeckal G. Harikumar
- , Sarah J. Piper
- & Laurence J. Miller
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Article
| Open AccessA rationally designed miniature of soluble methane monooxygenase enables rapid and high-yield methanol production in Escherichia coli
Soluble methane monooxygenase (sMMO) is a potentially value biocatalyst, but production of active recombinant sMMO is very challenging. Here the authors report the rational design and construction of a catalytically active miniature sMMO which enables high-yield production of methanol in E. coli.
- Yeonhwa Yu
- , Yongfan Shi
- & Jeewon Lee
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Article
| Open AccessAngle between DNA linker and nucleosome core particle regulates array compaction revealed by individual-particle cryo-electron tomography
Here, using cryo-ET, the 3D structures of individual nucleosome particles were characterized to observe changes under varying ionic strengths and in the presence of protein H1, revealing key regulatory roles in chromatin organization dynamics.
- Meng Zhang
- , César Díaz-Celis
- & Gang Ren
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Article
| Open AccessStructure and inhibition of the human lysosomal transporter Sialin
Sialin transports multiple substrates including sialic acid out of lysosomes, and neurotransmitters into synaptic vesicles. This study reports the cryo-EM structures of Sialin in multiple states revealing its transport and pH-sensing mechanisms.
- Philip Schmiege
- , Linda Donnelly
- & Xiaochun Li
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Article
| Open AccessIn-depth organic mass cytometry reveals differential contents of 3-hydroxybutanoic acid at the single-cell level
Comprehensive single-cell metabolic profiling is critical for revealing phenotypic heterogeneity and elucidating the molecular mechanisms underlying biological processes. Here, the authors establish a novel single-cell metabolomics platform for in-depth organic mass cytometry.
- Shaojie Qin
- , Yi Zhang
- & Yu Bai
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Article
| Open AccessThe patatin-like protein PlpD forms structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane
The Omp85 superfamily is a widely distributed class of outer membrane proteins found in Gram-negative bacteria, mitochondria and chloroplasts. Here the authors show that PlpD has a different structure and topology than other Omp85 proteins that have been studied.
- Sarah E. Hanson
- , Tyrone Dowdy
- & Harris D. Bernstein
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Article
| Open AccessSolutes unmask differences in clustering versus phase separation of FET proteins
Biomolecular condensates form via phase separation of multivalent macromolecules. Phase separation is governed by solubility whereas multivalence drives percolation, also known as gelation. The authors in this work identify the distinct energy and length scales that influence phase separation versus percolation.
- Mrityunjoy Kar
- , Laura T. Vogel
- & Rohit V. Pappu
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Article
| Open AccessCystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region
Here the authors use phage display to develop cystine-knot peptides that inhibit the trimeric serine protease HTRA1. Structural and biochemical characterisation uncovered binding of the peptides to a cryptic pocket that locked the active site in a noncompetent state.
- Yanjie Li
- , Yuehua Wei
- & Daniel Kirchhofer
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Article
| Open AccessDual-mode harvest solar energy for photothermal Cu2-xSe biomineralization and seawater desalination by biotic-abiotic hybrid
Biotic-abiotic photosynthetic systems hold great promise to innovate solar-driven chemical transformation. Here, the authors construct a biotic-abiotic hybrid system composed of Shewanella oneidensis MR-1 and biogenic Se0 nanoparticles for photothermal Cu2-xSe biomineralization and then for seawater desalination.
- Sheng-Lan Gong
- , YangChao Tian
- & Li-Jiao Tian
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Article
| Open AccessIntegrating cryo-OrbiSIMS with computational modelling and metadynamics simulations enhances RNA structure prediction at atomic resolution
Conventional structural biology techniques are limited in deciphering complex RNA structures and dynamic interactions. Here the authors show an integrated approach that combines cryogenic OrbiSIMS (cryo-OrbiSIMS) with computational methods for modelling RNA structures at atomic resolution.
- Shannon Ward
- , Alex Childs
- & Aditi N. Borkar
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Article
| Open AccessThe SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B
Here authors identify the interaction between the SUN-family protein Sad1 and histone H2A-H2B in S. pombe, and reveal the roles of the Sad1-histone interaction in the association of heterochromatin with the nuclear envelope and heterochromatin silencing.
- Wenqi Sun
- , Qianhua Dong
- & Yong Chen
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Article
| Open AccessReceptor-like cytoplasmic kinases of different subfamilies differentially regulate SOBIR1/BAK1-mediated immune responses in Nicotiana benthamiana
Cell-surface receptors form the front line of plant immunity. Here, the authors show that the RLP co-receptors SOBIR1 and BAK1 directly phosphorylate each other, leading to activation of the immune receptor complex in which RLCKs are differentially required for production of reactive oxygen species that play a role in resistance against Phytophthora palmivora.
- Wen R. H. Huang
- , Ciska Braam
- & Matthieu H. A. J. Joosten
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Article
| Open AccessCellular structure of dinosaur scales reveals retention of reptile-type skin during the evolutionary transition to feathers
The evolution of feathers is associated with the evolution of related skin microstructures. Here, the authors demonstrate that Psittacosaurus, a non-avian feathered dinosaur, retained scaled skin like its ancestors in body regions lacking feathers.
- Zixiao Yang
- , Baoyu Jiang
- & Maria E. McNamara
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Article
| Open AccessHeliorhodopsin-mediated light-modulation of ABC transporter
Here, authors classify genes flanking the Heliorhodopsin (HeR)-encoding genes and identify highly conserved residues for protein–protein interactions, revealing a function of HeR as regulatory rhodopsin for multidrug resistance.
- Shin-Gyu Cho
- , Ji-Hyun Kim
- & Kwang-Hwan Jung
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Article
| Open AccessEmergent ribozyme behaviors in oxychlorine brines indicate a unique niche for molecular evolution on Mars
Mars, an attractive candidate for potential presence of extraterrestrial life, contains oxychlorine species such as perchlorate at its surface. Here, the authors show perchlorate brines support folding and catalysis of functional RNAs, while inactivating representative protein enzymes, and that perchlorate enables new ribozyme functions, including ribozyme catalyzed chlorination of organic molecules.
- Tanner G. Hoog
- , Matthew R. Pawlak
- & Aaron E. Engelhart
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessMitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk
This study uses cryo-EM, biochemical, and computational approaches to shed light on the fundamental mechanisms underlying the human mitoribosome function, including ligand binding, modifications, Fe-S clusters, and aging-related polyamines.
- Vivek Singh
- , Yuzuru Itoh
- & Alexey Amunts
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Article
| Open AccessFatal COVID-19 pulmonary disease involves ferroptosis
Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.
- Baiyu Qiu
- , Fereshteh Zandkarimi
- & Brent R. Stockwell
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Article
| Open AccessPreserving ester-linked modifications reveals glutamate and aspartate mono-ADP-ribosylation by PARP1 and its reversal by PARG
Ester-linked modifications are common but difficult to detect. Here, the authors present methods based on ester preservation and a sensitive antibody to reveal DNA damage-induced mono-ADP-ribosylation on aspartate and glutamate. This signal, part of the first wave of PARP1 signaling, is removed by PARG.
- Edoardo José Longarini
- & Ivan Matić
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Article
| Open AccessBioinformatics leading to conveniently accessible, helix enforcing, bicyclic ASX motif mimics (BAMMs)
Researchers mimic protein interface helices by stapling peptide side chains, or replacing hydrogen bonds with covalent ones, and synthetic helical mimics are heavily biased towards stapling. Here the authors describe bioinformatic discovery of hydrophobic triangles at helix N-termini, and rigid, bicyclic synthetic mimics of them.
- Tianxiong Mi
- , Duyen Nguyen
- & Kevin Burgess
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Article
| Open AccessThe 8-17 DNAzyme can operate in a single active structure regardless of metal ion cofactor
Here, the authors use solution-state NMR to characterize the structure of 8–17 DNAzyme, revealing that all metal cofactors induce the same DNAzyme fold in contrast to previous findings.
- Julia Wieruszewska
- , Aleksandra Pawłowicz
- & Witold Andrałojć
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Article
| Open AccessExon-junction complex association with stalled ribosomes and slow translation-independent disassembly
Bensaude et al. use a split luciferase approach to show that exon-junction complex assembly and disassembly occur faster when they are translation-dependent than when they are translation-independent; and they uncover an association with ribosomes.
- Olivier Bensaude
- , Isabelle Barbosa
- & Hervé Le Hir
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