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| Open AccessBioorthogonal photocatalytic proximity labeling in primary living samples
Studying subcellular proteomes in primary living cells is crucial for understanding health and disease. Here, the authors introduce CAT-S, a non-genetic method based on photocatalysis, enabling in situ deciphering of mitochondrial proteomes in primary cells from mouse tissues and human blood.
- Ziqi Liu
- , Fuhu Guo
- & Xinyuan Fan
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessDiverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
Controlling copper levels is essential for life, causing disease when impaired. Here, structures of a copper transporter sheds light on the function of its metal binding domains and unifies previous theories on the details of copper transport.
- Zongxin Guo
- , Fredrik Orädd
- & Pontus Gourdon
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Article
| Open AccessPhosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li
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Article
| Open AccessInsights into the modulation of bacterial NADase activity by phage proteins
The defense-associated sirtuin 2 (DSR2) effector protects bacteria from phage infection by depleting NAD+. Here, the authors employ biochemical and structural approaches to reveal the inhibition and activation mechanisms of DSR2 by the phage anti-DSR2 protein (DSAD1) and tail tube protein (TTP).
- Hang Yin
- , Xuzichao Li
- & Heng Zhang
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Article
| Open AccessStructure of the intact tail machine of Anabaena myophage A-1(L)
The Myoviridae cyanophage A-1(L) specifically infects the model cyanobacteria Anabaena sp. PCC 7120. Here, authors present the high-resolution cryo-EM structure of its intact tail machine, and identify multiple hydrolytic and binding modules.
- Rong-Cheng Yu
- , Feng Yang
- & Cong-Zhao Zhou
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Article
| Open AccessDiverging co-translational protein complex assembly pathways are governed by interface energy distribution
Protein complex assembly can occur co-translationally. Here, the authors uncover diverging assembly pathways and hotspot disruptions in N-terminal acetyltransferases, enzymes implicated in neurodegenerative diseases. Their model predicts co-translational assembly based on interface energy distribution.
- Johannes Venezian
- , Hagit Bar-Yosef
- & Ayala Shiber
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Article
| Open AccessSolar-driven sugar production directly from CO2 via a customizable electrocatalytic–biocatalytic flow system
Solar-driven artificial food synthesis from CO2 provides an approach to overcome the limitations of natural photosynthesis, but it is very challenging. Here, the authors report a hybrid electrocatalytic-biocatalytic flow system, coupling photovoltaics-powered electrocatalysis (CO2 to formate) with a five enzyme cascade platform (formate to sugar), which achieves conversion of CO2 to C6 sugar (L-sorbose) with a solar-to-food energy conversion efficiency of 3.5%.
- Guangyu Liu
- , Yuan Zhong
- & Yujie Xiong
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Article
| Open AccessActivation of the insulin receptor by insulin-like growth factor 2
IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.
- Weidong An
- , Catherine Hall
- & Eunhee Choi
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Article
| Open AccessBidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA
ABC transporters are generally considered to be unidirectional. Here, the authors develop a fluorescence-based transport assay and show that the mycobacterial ABC transporter BacA instead acts as a bidirectional transporter for cobalamin.
- Mark Nijland
- , Solène N. Lefebvre
- & Dirk J. Slotboom
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Article
| Open AccessPredicting nuclear G-quadruplex RNA-binding proteins with roles in transcription and phase separation
RNA G-quadruplexes are important regulatory elements, yet our knowledge of their structure-based interactions is at present limited. Here the authors combine experimental and computational methods to develop a predictive tool, G4-FUNNIES, to estimate proteins’ RNA G4-binding propensities.
- Johanna Luige
- , Alexandros Armaos
- & Ulf Andersson Vang Ørom
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Article
| Open AccessStructural basis for peroxidase encapsulation inside the encapsulin from the Gram-negative pathogen Klebsiella pneumoniae
Peroxidase encapsulins are self-assembling protein compartments involved in oxidative stress response found in many pathogens. Here, the authors characterize the structural basis of peroxidase encapsulation inside the Klebsiella pneumoniae encapsulin.
- Jesse A. Jones
- , Michael P. Andreas
- & Tobias W. Giessen
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Article
| Open AccessA concise and scalable chemoenzymatic synthesis of prostaglandins
Prostaglandins are of interest to synthetic chemists due to their biological activities. Here, the authors present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps, via the common intermediate bromohydrin, a radical equivalent of Corey lactone.
- Yunpeng Yin
- , Jinxin Wang
- & Jian Li
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Article
| Open AccessMutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
ATGL is a key enzyme in intracellular lipolysis. Here, the authors use deep mutational scanning to define the determinants of protein interaction between ATGL and its regulatory partners, gaining insights into lipolysis mechanisms in cells.
- Johanna M. Kohlmayr
- , Gernot F. Grabner
- & Ulrich Stelzl
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Article
| Open AccessThe binding and mechanism of a positive allosteric modulator of Kv3 channels
To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.
- Qiansheng Liang
- , Gamma Chi
- & Manuel Covarrubias
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Article
| Open AccessA structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.
- Xiuxiu Lu
- , Monika Chandravanshi
- & Kylie J. Walters
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Article
| Open AccessTgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape
Development of hindlimbs and external genitalia share several regulatory factors. Lozovska et al. show that Tgfbr1 controls the response to those factors; embryos lacking Tgfbr1 develop two sets of hindlimbs at the expense of the external genitalia.
- Anastasiia Lozovska
- , Artemis G. Korovesi
- & Moisés Mallo
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Article
| Open AccessWidespread extracellular electron transfer pathways for charging microbial cytochrome OmcS nanowires via periplasmic cytochromes PpcABCDE
How do cells put electrons to rest? Using a minimal pathway to get rid of excess metabolic electrons, diverse environmentally important microbes overcome large spatial, kinetic, and thermodynamic barriers in order to survive in extreme anoxic conditions.
- Pilar C. Portela
- , Catharine C. Shipps
- & Nikhil S. Malvankar
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Article
| Open AccessThe evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba
Diels-Alderases (DAs), enzymes catalyzing [4 + 2] cycloaddition reactions, are of high interest, but insights into their evolution are lacking. Here, the authors investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites, suggesting they evolved from an ancestor functioning as a flavin adenine dinucleotide-dependent oxidocyclase.
- Qi Ding
- , Nianxin Guo
- & Xiaoguang Lei
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Article
| Open AccessStructure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP
Hepatitis B and D viruses require docking to the NTCP receptor protein for cell entry, an interaction that can be blocked by the drug bulevirtide. Here the authors use cryo-EM to reveal the structural basis of bulevirtide activity.
- Hongtao Liu
- , Dariusz Zakrzewicz
- & Kaspar P. Locher
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Article
| Open AccessStructural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor
The histamine H4 receptor (H4R) plays key roles in immune cell function. Here, the authors report structures of H4R-Gi complex with various ligands bound, revealing distinct ligand binding modes and a basis for rational design of novel antihistamines targeting H4R.
- Ruixue Xia
- , Shuang Shi
- & Yuanzheng He
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Article
| Open AccessRab GTPases and phosphoinositides fine-tune SNAREs dependent targeting specificity of intracellular vesicle traffic
Targeting of transport vesicles requires specific proteins and membrane lipids. Here, authors microinjected liposomes with a predetermined composition to show that targeting by SNAREs is refined when polyphosphoinositides and Rab GTPases are included.
- Seiichi Koike
- & Reinhard Jahn
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Article
| Open AccessStructure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface
KATP channels regulate insulin secretion and are activated by PIP2. Here, the authors show PIP2 binds between SUR1 and Kir6.2 to open the channel, and a neonatal diabetes mutation stabilizes KATP channels in a PIP2-bound open conformation.
- Camden M. Driggers
- , Yi-Ying Kuo
- & Show-Ling Shyng
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Article
| Open AccessDissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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Article
| Open AccessActivation and friction in enzymatic loop opening and closing dynamics
Enzymes present loops around active sites whose closing and opening dynamics are essential for its activity. Here the authors unveil the mechanism governing loop motion, showing that it involves an activated conformational rearrangement around a couple of torsional angles taking place under the strong friction exerted by the rest of loop torsions.
- Kirill Zinovjev
- , Paul Guénon
- & Iñaki Tuñón
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Article
| Open AccessPrediction of glycopeptide fragment mass spectra by deep learning
Deep learning has achieved a notable success in proteomics and is now emerging in glycoproteomics. Here, the authors develop a neural network-based method to predict mass spectra of intact glycopeptides and demonstrate its potential in data-dependent and data-independent acquisition glycoproteomics.
- Yi Yang
- & Qun Fang
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Article
| Open AccessLegionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain
The pathogen Legionella pneumophila mediates NAD+-dependent ubiquitination pathways upon infection. Here, the authors show the Legionella effector MavL reverses ubiquitin ADP-ribosylation to regulate these pathways. MavL represents a new macrodomain class specific for reversal of arginine ADP-ribosylation with distinct ADP-ribose binding features.
- Zhengrui Zhang
- , Jiaqi Fu
- & Chittaranjan Das
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Article
| Open AccessTwo DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessVCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates
p97/VCP, a nexus of the ubiquitin system, recognizes and unfolds ubiquitylated substrates via multiple cofactors. Here, the authors identify VCF1, a nuclear cofactor promoting p97 recruitment to, and proteasomal degradation of, ubiquitylated targets.
- Ann Schirin Mirsanaye
- , Saskia Hoffmann
- & Niels Mailand
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Article
| Open AccessNMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection
Metabolic changes often occur during the early stages of cancer development. Here, the authors develop metabolomics signatures from tissues, pre- and post-operative sera and urines in esophageal squamous cell carcinoma, which may aid in early diagnosis.
- Yan Zhao
- , Changchun Ma
- & Yan Lin
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Article
| Open AccessHTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Sheng Chen
- , Anuradhika Puri
- & Meredith E. Jackrel
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Article
| Open AccessMesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes
Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer. This study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their substrate selectivity.
- Ambrocio Sanchez
- , Pedro Ortega
- & Rémi Buisson
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Article
| Open AccessNAP-seq reveals multiple classes of structured noncoding RNAs with regulatory functions
The genome-wide prevalence, mechanism and function of noncapped RNAs (napRNAs) are currently poorly understood. Here, the authors develop a method called NAP-seq, to globally profile the full-length sequences of napRNAs, revealing several classes of structured noncoding RNAs.
- Shurong Liu
- , Junhong Huang
- & Jianhua Yang
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Article
| Open AccessStructural and mechanistic insights into activation of the human RNA ligase RTCB by Archease
RTCB-type RNA ligases play important roles in tRNA splicing, the unfolded protein response and RNA repair. Here, Gerber et al. present structural snapshots of RTCB’s reaction cycle, and show how an activation complex with Archease primes RTCB for ligation.
- Janina Lara Gerber
- , Suria Itzel Morales Guzmán
- & Jirka Peschek
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Article
| Open AccessStructure of full-length ERGIC-53 in complex with MCFD2 for cargo transport
ERGIC-53 engages in the ER-to-Golgi transport of secretory and membrane proteins by unknown mechanisms. Here authors report a long flexible tetrameric structure of full-length ERGIC-53 complexed with its functional partner MCFD2 by cryo-EM.
- Satoshi Watanabe
- , Yoshiaki Kise
- & Kenji Inaba
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Article
| Open AccessStructural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1
Yeast cadmium factor 1 (Ycf1), a heavy metal and glutathione transporter, is regulated by an intrinsically disordered region called the regulatory domain. In this work, the authors show that this domain controls activity through autoinhibition of the glutathione cavity when it is dephosphorylated.
- Nitesh Kumar Khandelwal
- & Thomas M. Tomasiak
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Article
| Open AccessBiosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol
Despite intensive investigation, stepwise reactions from diol to Taxol tetracyclic core skeleton remain unclear. Here, authors fill this gap by identifying two P450s and confirming the reaction order.
- Chengshuai Yang
- , Yan Wang
- & Zhihua Zhou
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Article
| Open AccessDual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin
The poison dart toxin batrachotoxin is the most lethal voltage-gated sodium channel toxin. Here authors identify the toxin bound specifically at two homologous receptor sites, which cause channel hyperactivation by positively modulating channel gating and altering ion conductance.
- Lige Tonggu
- , Goragot Wisedchaisri
- & William A. Catterall
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Article
| Open AccessThermophoretic glycan profiling of extracellular vesicles for triple-negative breast cancer management
Triple-negative breast cancer (TNBC) lacks precise diagnostic and monitoring methods due to limited biomarkers. Here the authors develop a lectin-based thermophoretic assay (EVLET) that combines vibrating membrane filtration and thermophoretic amplification for efficient extracellular vesicle (EV) glycan profiling in the plasma of TNBC patients, enabling non-invasive cancer management by leveraging EV glycans.
- Yike Li
- , Shaohua Zhang
- & Jiashu Sun
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Article
| Open AccessRegulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2
Meiosis is a specialized cell division for generating germ cells. The authors show that the lipid composition in the cellular membrane influences meiosis-specific chromosomal dynamics in mouse testis.
- Jingjing Zhang
- , Mario Ruiz
- & Hiroki Shibuya
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Article
| Open AccessSupra-biological performance of immobilized enzymes enabled by chaperone-like specific non-covalent interactions
Designing complex synthetic materials for enzyme immobilization could unlock the utility of biocatalysis in extreme environments. Here, the authors report on random copolymer brushes as dynamic immobilization supports that enable supra-biological catalytic performance of immobilized enzymes.
- Héctor Sánchez-Morán
- , Joel L. Kaar
- & Daniel K. Schwartz
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Article
| Open AccessHigh-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design
Discovery of new therapeutics has been hampered by the often-limiting resolution and throughput of cryo-EM. Here, the authors determine high-resolution cryo-EM structures of the CDK-activating kinase to establish a methodological framework for the use of cryo-EM in structure-based drug design.
- Victoria I. Cushing
- , Adrian F. Koh
- & Basil J. Greber
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Article
| Open AccessStructural characterization of the oligomerization of full-length Hantaan virus polymerase into symmetric dimers and hexamers
Hantaan virus polymerase is a central enzyme that performs hantavirus genome replication and transcription. Here, the authors unveil the structure of the full-length Hantaan virus polymerase in monomeric, dimeric and hexameric apo forms, revealing the multimerization capability of this enzyme.
- Quentin Durieux Trouilleton
- , Dominique Housset
- & Hélène Malet
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Article
| Open AccessToll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity
Toll/interleukin-1 receptor domain-containing proteins can catabolize NAD+. Here, Wang et al show that these proteins can also function as NAD-RNA decapping enzymes by releasing the NAM moiety from the NAD-RNA, resulting in the regulation of gene expression.
- Xufeng Wang
- , Dongli Yu
- & Xuemei Chen
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Article
| Open AccessStructure-based prediction and characterization of photo-crosslinking in native protein–RNA complexes
Feng et al. developed a computational method PxR3D-map to jointly analyze crosslinked nucleotides and amino acids in protein-RNA complexes, which revealed key structural features underlying photocrosslinking of protein and RNA in cells.
- Huijuan Feng
- , Xiang-Jun Lu
- & Chaolin Zhang
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Article
| Open AccessFunctionalized graphene-oxide grids enable high-resolution cryo-EM structures of the SNF2h-nucleosome complex without crosslinking
Nucleosome-protein complexes stick to the air-water interface and denature upon plunge freezing for cryoEM. Here, authors Chio and Palovcak et al. develop EM grids that protect such complexes and use these grids to study the ATP-dependent chromatin remodeler SNF2h.
- Un Seng Chio
- , Eugene Palovcak
- & Yifan Cheng
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Article
| Open AccessSubstrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10
Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.
- Kevin Wu
- , Samuel Itskanov
- & Eunyong Park
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Article
| Open AccessLipoarabinomannan mediates localized cell wall integrity during division in mycobacteria
Mycobacteria have a unique cell envelope that includes characteristic lipoglycans, such as lipoarabinomannan. Here, Sparks et al. show that this lipoglycan plays roles in maintenance of local cell envelope integrity and septal placement during cell division.
- Ian L. Sparks
- , Takehiro Kado
- & Yasu S. Morita
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