Featured
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Article
| Open AccessNucleic acid mediated activation of a short prokaryotic Argonaute immune system
The SPARTA defense system, activated by invading DNA for NAD(P)+ hydrolysis, was recently identified in bacteria. Here, authors visualize SPARTA before and after nucleic acid binding and uncover the basis of its active assembly leading to abortive infection.
- Jithesh Kottur
- , Radhika Malik
- & Aneel K. Aggarwal
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Article
| Open AccessPNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein
The PNPLA3 gene is associated with fatty liver disease. Here, the authors define a role for PNPLA3 as a polyunsaturated triglyceride lipase that maintains the balance between hepatic triglyceride storage and secretion.
- Scott M. Johnson
- , Hanmei Bao
- & Jun Liu
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Article
| Open AccessStructural basis of promoter recognition by Staphylococcus aureus RNA polymerase
Here, Yuan, Liu, and Xu et al. report cryo-EM structures of Staphylococcus aureus RNAP-promoter open complexes, highlighting distinct interactions of σA and σB with their cognate promoters.
- Linggang Yuan
- , Qingyang Liu
- & Yu Feng
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Article
| Open AccessInhibition and transport mechanisms of the ABC transporter hMRP5
Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. Here, the authors present cryo-EM structures of hMRP5 in different states, showing that hMRP5 can be autoinhibited by a short peptide from its N-terminal tail, which prevents the entry of substrates into hMRP5’s transport pathway.
- Ying Huang
- , Chenyang Xue
- & Zhongmin Liu
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Article
| Open AccessThe manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease
The metal transporter SLC39A8 is linked to blood manganese (Mn) levels and inflammatory bowel diseases (IBD). Here, the authors show that loss of SLC39A8 impairs intestinal Mn absorption and epithelial integrity, suggesting potential therapeutic strategies targeting alkaline ceramidase 1 for IBD patients with SLC39A8 deficiency.
- Eun-Kyung Choi
- , Thekkelnaycke M. Rajendiran
- & Young Ah Seo
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Article
| Open AccessStructure and mechanism of the K+/H+ exchanger KefC
Intracellular potassium (K+) homeostasis is achieved by activity of both ion channels and transporters. Here, the authors report structures of E. coli glutathione (GSH)-gated K+ efflux transporter KefC with bound K+ and conclude that the ion-binding site is adapted for binding a dehydrated ion.
- Ashutosh Gulati
- , Surabhi Kokane
- & David Drew
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Article
| Open AccessPotent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A
Polymyxins are last-resort antibiotics targeting lipid A in the gram-negative outer membrane. Here, the authors use surface plasmon resonance-based kinetics to reveal a three-state mechanism governing superstoichiometric accumulation of polymyxins.
- Kerry R. Buchholz
- , Mike Reichelt
- & John G. Quinn
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Article
| Open AccessLipid unsaturation promotes BAX and BAK pore activity during apoptosis
BAX and BAK are proapoptotic proteins that directly mediate mitochondrial outer membrane permeabilization (MOMP). Here, lipidomics and other data provide insight on how local lipid environment affects BAX and BAK function during apoptosis, suggesting that unsaturated lipids promote BAX pore activity.
- Shashank Dadsena
- , Rodrigo Cuevas Arenas
- & Ana J. García-Sáez
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Article
| Open AccessIdentification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease
Diagnostic blood-based biomarkers of pediatric IBD are limited. Here, the authors demonstrate a diagnostic lipidomic signature, comprising only of two molecular lipids. Translation of this signature into a scalable test has the potential to support clinical decision making.
- Samira Salihovic
- , Niklas Nyström
- & Jonas Halfvarson
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Article
| Open AccessHighly biased agonism for GPCR ligands via nanobody tethering
Activated GPCRs signal through multiple pathways. Ligands that signal through a single pathway are highly valued. The authors demonstrate that tethering ligands to receptors via conjugation with binding nanobodies enables pathway-specific signaling.
- Shivani Sachdev
- , Brendan A. Creemer
- & Ross W. Cheloha
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Article
| Open AccessConformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate
How folded proteins are translocated across membranes is unknown for eukaryotes. Here, the authors propose a concerted translocation mechanism used by the AAA-ATPase Bcs1 to retro-translocate fully folded Rieske iron-sulfur protein across mitochondrial inner membrane.
- Jingyu Zhan
- , Allison Zeher
- & Di Xia
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Article
| 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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