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| Open AccessIdentification of global inhibitors of cellular glycosylation
Here, the authors discover small molecules that inhibit glycosylation processes that occur in the Golgi apparatus of cells. The molecules reversibly inhibit formation of elaborate glycan structures without affecting secretion of glycoproteins.
- Daniel Madriz Sørensen
- , Christian Büll
- & Yoshiki Narimatsu
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| Open AccessCryo-EM reveals the molecular basis of laminin polymerization and LN-lamininopathies
In this work the authors report the cryo-EM structure of the laminin polymer node and reveal the molecular basis of calcium-dependent formation of laminin lattice. The work provides insights into laminin polymerization defects manifesting in human disease.
- Arkadiusz W. Kulczyk
- , Karen K. McKee
- & Peter D. Yurchenco
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| Open AccessCell-specific bioorthogonal tagging of glycoproteins
Changes in glycoprotein expression are correlates of disease, but secreted glycoproteins cannot be accurately traced to their cell line of origin. Here, the authors develop a strategy to chemically tag and profile glycoproteins in a cell line-specific manner in co-culture systems and in vivo.
- Anna Cioce
- , Beatriz Calle
- & Benjamin Schumann
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| Open AccessGlobal mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line
Information about O-glycosylation site regulation and occupancy in the human proteome is limited. Here, the authors identify GalNAc transferase-specific glycan sites in human keratinocytes and describe their occupancy.
- Mathias I. Nielsen
- , Noortje de Haan
- & Hans H. Wandall
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| Open AccessCharacterization of core fucosylation via sequential enzymatic treatments of intact glycopeptides and mass spectrometry analysis
Core fucosylation of N-linked glycoproteins has been linked to physiological and pathological processes. Here, the authors develop a mass spectrometry-based method that utilizes Endo F3 followed by PNGase F treatment to quantify site-specific glycoprotein core fucosylation in protein mixtures.
- Liwei Cao
- , T. Mamie Lih
- & Hui Zhang
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| Open AccessGlyco-Decipher enables glycan database-independent peptide matching and in-depth characterization of site-specific N-glycosylation
Poor peptide fragmentation and unusual glycan structures limit mass spectrometry-based analysis of intact N-glycopeptides. Here, the authors develop Glyco-Decipher, a glycan-independent peptide search tool, to tackle these issues and improve the coverage of site-specific glycan analysis.
- Zheng Fang
- , Hongqiang Qin
- & Mingliang Ye
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Article
| Open AccessDisplay of the human mucinome with defined O-glycans by gene engineered cells
Mucins play critical roles in maintaining the human microbiome, with their O-glycosylated tandem repeats (TRs) providing important cues for microbiota. Here, the authors develop a cellular platform for producing TRs with defined O-glycan structures to dissect the functions of TR O-glycosylation.
- Rebecca Nason
- , Christian Büll
- & Yoshiki Narimatsu
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| Open AccessHigh-resolution ex vivo NMR spectroscopy of human Z α1-antitrypsin
α1-Antitrypsin (AAT) is a 52 kDa serum glycoprotein, the misfolding and polymerisation of which is associated with COPD and liver disease. Here the authors demonstrate the use of high-resolution multidimensional solution-state NMR spectroscopy to characterise the structure and dynamics in solution of Z AAT purified directly from clinical patients.
- Alistair M. Jagger
- , Christopher A. Waudby
- & David A. Lomas
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| Open AccessA streamlined pipeline for multiplexed quantitative site-specific N-glycoproteomics
Comprehensive quantitative profiling of intact glycopeptides remains technically challenging. To address this, the authors here develop an integrated quantitative glycoproteomic workflow, including optimized sample preparation, multiplexed quantification and a dedicated data processing tool.
- Pan Fang
- , Yanlong Ji
- & Henning Urlaub
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Article
| Open AccessVulnerabilities in coronavirus glycan shields despite extensive glycosylation
Glycosylation plays a key role in shielding of immunogenic epitopes on viral spike (S) proteins. Here Watanabe et al. report that glycans of coronavirus SARS and MERS S proteins are heterogeneously distributed and do not form an efficacious high-density global shield which would ensure efficient immune evasion.
- Yasunori Watanabe
- , Zachary T. Berndsen
- & Max Crispin
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Article
| Open AccessGlycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses
Influenza virus hemagglutinin (HA) stem between group 1 and 2 viruses has different glycosylation patterns, likely hampering cross-group protection. Here, Boyoglu-Barnum et al. show that introducing a group 2 glycan into a group 1 stem nanoparticle vaccine broadens antibody responses in mice to cross-react with group 2 HAs.
- Seyhan Boyoglu-Barnum
- , Geoffrey B. Hutchinson
- & Masaru Kanekiyo
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Article
| Open AccessElimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
Mutations in Ftkn cause Fukuyama muscular dystrophy, and heart failure is the main cause of death in thes patients. Here the authors show that acute elimination of Fktn in adult mice causes early mortality, and this is associated with myocyte dysfunction, with disorganised Golg-microtubule networks, and that the pathology can be ameliorated with colchicine treatment.
- Yoshihiro Ujihara
- , Motoi Kanagawa
- & Yuki Katanosaka
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| Open AccessNext-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells
Per-O-acetylated unnatural monosaccharides are popular tools for glycan labeling in live cells but can undergo unwanted side reactions with cysteines. Here, the authors develop unnatural sugars in a partially esterified form that are inert towards cysteines, and use them to probe O-GlcNAcylation in mESCs.
- Yi Hao
- , Xinqi Fan
- & Xing Chen
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Article
| Open AccessMolecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
Glycoprotein ZP1 is a component of the oocyte’s zona pellucida (ZP), and mutations in human ZP1 are linked to female infertility. Here, using structure-function analysis, the authors suggest that filament cross-linking by ZP1 is required to form a stable ZP in human, and infertility mutations interfere with cross-linking.
- Kaoru Nishimura
- , Elisa Dioguardi
- & Luca Jovine
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| Open AccessAn enrichment method based on synergistic and reversible covalent interactions for large-scale analysis of glycoproteins
Understanding the functions of protein glycosylation critically depends on methods to efficiently enrich glycoproteins from complex samples. Here, the authors develop a strategy using dendrimer-conjugated benzoboroxole to enhance glycopeptide enrichment, providing the basis for more comprehensive glycoprotein analyses.
- Haopeng Xiao
- , Weixuan Chen
- & Ronghu Wu
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Article
| Open AccessStructural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope
Structure determination of glycosylated HIV-1 envelope (Env) trimers complexed with broadly neutralizing antibodies (bNAbs) promotes a better understanding of bNAb epitopes. Here the authors present the structures of natively-glycosylated Env in complex with the highly-potent bNAb BG18, which is of interest for HIV-1 vaccine development.
- Christopher O. Barnes
- , Harry B. Gristick
- & Pamela J. Bjorkman
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| Open AccessTemporal regulation of Lsp1 O-GlcNAcylation and phosphorylation during apoptosis of activated B cells
B cell receptor (BCR) activation can trigger signalling causing apoptosis in order to eliminate auto-reactive B cells. Here the authors show that the O-GlcNAcylation and phosphorylation of lymphocyte-specific protein-1 are involved in a switch that regulates the initiation of apoptosis induced by BCR cross-linking.
- Jung-Lin Wu
- , Hsin-Yi Wu
- & Kuo-I. Lin
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Article
| Open AccessTenascin-C drives persistence of organ fibrosis
Systemic sclerosis (SSc) is a fibrotic disease affecting multiple organs. Here the authors use patient samples plus mouse studies to show a central role for tenascin C as a TLR4 activator responsible for persistence of fibrosis in the context of SSc and SSc-like disease.
- Swati Bhattacharyya
- , Wenxia Wang
- & John Varga
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Article
| Open Accessklf2a couples mechanotransduction and zebrafish valve morphogenesis through fibronectin synthesis
In the developing heart, blood flow transmits mechanical signals to progenitor cells that ultimately leads to valve formation. Here, the authors identify the origin of the valve progenitor cells and fibronectin1bas a transcriptional target of the mechanotransduced signals responsible for valve formation.
- Emily Steed
- , Nathalie Faggianelli
- & Julien Vermot
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| Open AccessAn inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination
Chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes are known to inhibit OPC differentiation and remyelination. Here, the authors identify a novel CSPG synthesis inhibitor and find it can rescue OPC differentiation in vitroand accelerate remyelination in mice following focal demyelination.
- Michael B. Keough
- , James A. Rogers
- & V. Wee Yong
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Article
| Open AccessStabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration
Phosphatidylserine and its receptors are associated with cell-cell fusion. Here, the authors show the phosphatidylserine receptor stabilin-2 is expressed by muscle cells and plays a vital role in myoblast fusion and post-injury muscle regeneration in mice.
- Seung-Yoon Park
- , Youngeun Yun
- & In-San Kim
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Article
| Open AccessStructure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody
Cytomegalovirus is a danger to individuals with compromised immune systems and neonates infected in utero. Here the authors show the structure of a neutralizing antibody-bound viral fusion protein glycoprotein B, supporting the development of therapeutic antibodies and vaccines.
- Sumana Chandramouli
- , Claudio Ciferri
- & Andrea Carfi
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| Open AccessBlood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation
Autoimmune brain inflammation is associated with activation of macrophages and microglia. Here the authors show that fibrinogen induces encephalitogenic T-cell activation and macrophage recruitment to the central nervous system, and promotes demyelination in a mouse model of multiple sclerosis.
- Jae Kyu Ryu
- , Mark A. Petersen
- & Katerina Akassoglou
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Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol
The GP protein of the Ebola virus is involved in the detachment of infected cells, which eventually leads to vascular leakage and contributes to haemorrhagic fever. Here Hacke et al.show that the membrane-anchored subunit of GP is sufficient to induce cell detachment, and that cholesterol contributes to this process.
- Moritz Hacke
- , Patrik Björkholm
- & Andreas M. Ernst
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Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma
Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.
- Bo-Kyung Son
- , Daigo Sawaki
- & Toru Suzuki
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| Open AccessVirus-like glycodendrinanoparticles displaying quasi-equivalent nested polyvalency upon glycoprotein platforms potently block viral infection
Host–pathogen relationships can be mediated by polyvalent glycan ligand–protein interactions. Here well-defined highly valent glycodendrimeric constructs are synthesized that can mimic pathogens, and can inhibit a model of infection by the Ebola virus.
- Renato Ribeiro-Viana
- , Macarena Sánchez-Navarro
- & Benjamin G. Davis
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Visualizing specific protein glycoforms by transmembrane fluorescence resonance energy transfer
A common post-translational modification is the attachment of sugars, but proteins with different sugar chains, known as glycoforms, are hard to distinguish. Here, the authors use transmembrane fluorescence resonance energy transfer to visualize specific glycoforms of the membrane protein GLUT4 in living cells.
- Yoshimi Haga
- , Kumiko Ishii
- & Tadashi Suzuki
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Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion
Herpesvirus glycoprotein D binds to nectin 1 and the herpes virus entry mediator protein on the surface of host cells. In this study, Zhanget al. report the crystal structure of glycoprotein D in complex with the immunoglobulin-like domains of nectin 1, which suggests that binding of glycoprotein D to nectin 1 prevents nectin 1 dimerization.
- Na Zhang
- , Jinghua Yan
- & George F Gao