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Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity
Here, the authors show that GalNAc-T3 and T7 regulate furin cleavage of the SARS-CoV-2 spike protein via O-glycosylation. This influences viral assembly and infection, highlighting glycosylation as a host defense mechanism.
- Shengjun Wang
- , Wei Ran
- & Yang Mao
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Ion mobility-tandem mass spectrometry of mucin-type O-glycans
Currently, only a few specialized labs can characterize O-glycans. The present study couples high-resolution ion mobility spectrometry with tandem mass spectrometry to efficiently identify complex O-glycan structures in clinical samples.
- Leïla Bechtella
- , Jin Chunsheng
- & Kevin Pagel
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N-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line
IgG molecules are glycosylated at a conserved asparagine residue of their constant region, and this modification is essential for the effector functions of their soluble form, such as complement activation and binding to Fcɣ receptors. Here authors show that in a model B-cell line, neither the expression nor the function of the membrane-bound form of IgG depend on glycosylation.
- Theresa Kissel
- , Veerle F. A. M. Derksen
- & René E. M. Toes
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Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila
NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.
- Ashutosh Pandey
- , Antonio Galeone
- & Hamed Jafar-Nejad
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Chemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
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Identification 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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Altered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia
Raine syndrome is associated with loss-of-function mutations of FAM20C. Here we show that Raine-originated mutations abrogate the interaction between FAM20C and C4ST-1 to alter chondroitin sulfate sulfation status and impact biomineralization in vitro and bone mineral density in vivo in mouse models, thereby serving clues for Raine syndrome etiology.
- Toshiyasu Koike
- , Tadahisa Mikami
- & Hiroshi Kitagawa
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Structural insights into the contactin 1 – neurofascin 155 adhesion complex
In this work the authors show how a combination of glycosylations, rigid and flexible parts within neurofascin 155 and contactin 1 define a 7.4 nm distance at the myelin-axon interface and allow bridging of three-fold larger distances in the synapse.
- Lucas M. P. Chataigner
- , Christos Gogou
- & Bert J. C. Janssen
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Cell-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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Global 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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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway
Lysosomal biogenesis errors often result in diseases including mucolipidosis. Here Zhang and Yang et al. identify TMEM251/GCAF as a mannose-6-phosphate modification regulator that is necessary for correct lysosomal targeting, and classify Mucolipidosis Type V as resulting from GCAF mutations.
- Weichao Zhang
- , Xi Yang
- & Ming Li
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Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut
AM0627 is a bis-O-glycan mucinase that might work in the final steps of mucus degradation, thereby providing a carbon and nitrogen source for Akkermansia muciniphila. Here, the authors provide molecular insights into AM0627 function from X-ray crystallography and computer simulations.
- Víctor Taleb
- , Qinghua Liao
- & Ramon Hurtado-Guerrero
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Human-type sialic acid receptors contribute to avian influenza A virus binding and entry by hetero-multivalent interactions
It is believed that human Influenza HA glycoprotein attaches to alpha2-6 linked sialic acids (SA) on cells, while avian viruses bind to alpha2-3 linked sialic acids, therewith contributing to host tropism. Here, Liu et al. show that mixing low-affinity alpha2-3 SA with low amounts of high-affinity alpha2-6 SA increases binding and entry of human viruses and the converse for avian virus. This shows that receptor recognition is not as strict as currently assumed and provides evidence that heteromultivalent interactions between human/avian HA and SA contributes to host adaptation.
- Mengying Liu
- , Liane Z. X. Huang
- & Erik de Vries
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Characterization 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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Revealing the human mucinome
Mucin-domain glycoproteins are densely O-glycosylated proteins with unique secondary structure that imparts a large influence on cellular environments. Here, the authors develop a technique to selectively enrich and characterize mucin-domain glycoproteins from cell lysate and patient biofluids.
- Stacy A. Malaker
- , Nicholas M. Riley
- & Carolyn R. Bertozzi
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Genetic regulation of post-translational modification of two distinct proteins
Post-translational modifications are known to diversify protein functions, but the effect of genetic variation on the modifications is not well known. Here, the authors find both shared and protein-specific genetic mechanisms regulating the glycosylation of two different proteins.
- Arianna Landini
- , Irena Trbojević-Akmačić
- & Lucija Klarić
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Hexosamine biosynthetic pathway and O-GlcNAc-processing enzymes regulate daily rhythms in protein O-GlcNAcylation
Misalignment between lifestyle and the natural day-night cycle, such as mistimed eating, can negatively impact health. Here the authors show that mistimed feeding alters protein O-GlcNAcylation, a nutrient sensitive post-translational modification.
- Xianhui Liu
- , Ivana Blaženović
- & Joanna C. Chiu
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Display 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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Improving cell-free glycoprotein synthesis by characterizing and enriching native membrane vesicles
Cell-free gene expression systems are an attractive platform for biomanufacturing and synthetic biology. Here the authors characterize native membrane vesicles in E. coli extracts for improved glycoengineering.
- Jasmine M. Hershewe
- , Katherine F. Warfel
- & Michael C. Jewett
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Arabidopsis ACINUS is O-glycosylated and regulates transcription and alternative splicing of regulators of reproductive transitions
AtACINUS is an Arabidopsis homolog of a mammalian splicing regulator and previously found to be O-GlcNAcyated. Here Bi et al. characterize the interactors and targets of AtACINUS, show it is required for development and stress responses and provide evidence that its O-glycosylation affects alternative splicing.
- Yang Bi
- , Zhiping Deng
- & Zhi-Yong Wang
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Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways
Therapeutic angiogenesis has the potential of inducing and maintaining new blood vessels and thus improving outcomes in patients with ischemic disorders. Mannosamine functions as an endothelial cell mitogen/survival factor through activation of stress pathways and might be useful to protect and regenerate the vascular endothelium in a variety of disorders.
- Cuiling Zhong
- , Pin Li
- & Napoleone Ferrara
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Glycoproteomics-based signatures for tumor subtyping and clinical outcome prediction of high-grade serous ovarian cancer
Altered protein glycosylation is increasingly recognized as a hallmark of cancer. Here, the authors profile the glycoproteome of 119 high-grade serous ovarian carcinoma tissues, showing that glycosylation patterns correlate with tumor molecular subtypes and clinical outcomes.
- Jianbo Pan
- , Yingwei Hu
- & Hui Zhang
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An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles
O-glycosylation is an abundant post-translational modification but its relevance for bioactive peptides is unclear. Here, the authors detect O-glycans on almost one third of the classified peptide hormones and show that O-glycosylation can modulate peptide half-lives and receptor activation properties.
- Thomas D. Madsen
- , Lasse H. Hansen
- & Katrine T. Schjoldager
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Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis and ER-associated degradation
Glycosylphosphatidylinositol (GPI) anchors are found on many cell surface proteins but their biosynthesis is not fully understood. Here, the authors identify genes involved in GPI galactosylation and reveal functional connections between GPI processing, glycosphingolipid biosynthesis and ER-associated degradation.
- Yicheng Wang
- , Yusuke Maeda
- & Taroh Kinoshita
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Next-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
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Capturing site-specific heterogeneity with large-scale N-glycoproteome analysis
Mass spectrometry facilitates large-scale glycosylation profiling but in-depth analysis of intact glycopeptides is still challenging. Here, the authors show that activated ion electron transfer dissociation is suitable for glycopeptide fragmentation and improves glycoproteome coverage.
- Nicholas M. Riley
- , Alexander S. Hebert
- & Joshua J. Coon
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The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation
The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity.
- Bing Liu
- , Oscar C. Salgado
- & Hai-Bin Ruan
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Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice
Mutations in FKRP impair glycosylation of alpha-dystroglycan, leading to muscular dystrophy. Here, the authors show that oral administration of ribitol increases dystropglycan glycosylation and ameliorates symptoms of muscular dystrophy in FKRP-deficient mouse models.
- Marcela P. Cataldi
- , Peijuan Lu
- & Qi Long Lu
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Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer
Native-like soluble HIV envelope (Env) trimers are potential vaccine immunogens, and elimination of furin-dependence could provide a DNA-based alternative. Here, Sarkar et al. show that a cleavage-independent Env construct recapitulates the architecture and glycosylation of the native cleaved trimer.
- Anita Sarkar
- , Shridhar Bale
- & Ian A. Wilson
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STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion
PD-L1 accumulates on cancer stem cells and favours immune evasion but the mechanism underlying this accumulation are unknown. Here the authors show that epithelial-mesenchymal transition induces glycosylation and stabilisation of PD-L1; antagonising this process renders cancer cells sensitive to anti-Tim3-therapy.
- Jung-Mao Hsu
- , Weiya Xia
- & Mien-Chie Hung
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An 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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AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation
AMPK activation inhibits cardiac hypertrophy. Here the authors show that this occurs independently of previously proposed mechanisms and that AMPK controls the phosphorylation of the aminotransferase GFAT, thereby preventing cardiac hypertrophy through the reduction of protein O-GlcNAcylation.
- Roselle Gélinas
- , Florence Mailleux
- & Luc Bertrand
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Characterization of a membrane-bound C-glucosyltransferase responsible for carminic acid biosynthesis in Dactylopius coccus Costa
Carminic acid is a widely applied red colorant that is still harvested from insects because its biosynthesis is not fully understood. Here, the authors identify and characterize a membrane-bound C-glucosyltransferase catalyzing the final step during carminic acid biosynthesis.
- Rubini Kannangara
- , Lina Siukstaite
- & Birger Lindberg Møller
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Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis
Polη is a key player in translesion DNA synthesis. Here, the authors uncover that, in response to DNA damage, Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase to facilitate the timely disassembly of Polη after DNA lesion bypass.
- Xiaolu Ma
- , Hongmei Liu
- & Caixia Guo
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O-GlcNAcylation of SIRT1 enhances its deacetylase activity and promotes cytoprotection under stress
SIRT1 is a stress sensor whose deacetylase activity is increased during cellular stress, but the molecular mechanism is unclear. Here, the authors show that O-GlcNAcylation of SIRT1 is elevated upon different stress stimuli and increases SIRT1 deacetylase activity, protecting cells from stress-induced apoptosis.
- Cuifang Han
- , Yuchao Gu
- & Wengong Yu
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Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts
The role of O-glycosylation in the malaria life cycle is largely unknown. Here, the authors identify a Plasmodium protein O-fucosyltransferase and show that it is important for normal trafficking of a subset of surface proteins, particularly CSP and TRAP, and efficient infection of mosquito and vertebrate hosts.
- Sash Lopaticki
- , Annie S. P. Yang
- & Justin A. Boddey
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Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.
- Chia-Wei Li
- , Seung-Oe Lim
- & Mien-Chie Hung
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| Open Access
ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation
Here, Dirk Lefeber and colleagues identify functional mutations in ATP6AP1 encoding Ac45. The authors show that Ac45 is the functional ortholog of yeast V-ATPase assembly factor Voa1 and provide evidence for tissue-specific Ac45 processing, associated with the clinical phenotype of immunodeficiency, hepatopathy, and neurocognitive abnormalities.
- Eric J. R. Jansen
- , Sharita Timal
- & Dirk J. Lefeber
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ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan
Mutations in genes required for the glycosylation of α-dystroglycan lead to dystroglycanopathies. Here, the authors show that three of these enzymes (ISPD, FKTN and FKRP) work together to attach ribitol phosphate to α-dystroglycan.
- Isabelle Gerin
- , Benoît Ury
- & Guido T. Bommer
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Article
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O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth
The pentose phosphate pathway is aberrantly activated in cancer cells but the mechanism is unclear. Here, the authors show that G6PD, the rate-limiting enzyme in the pathway, is post-translationally modified with a sugar moiety under hypoxic conditions leading to increased production of precursors for macromolecular synthesis and antioxidants.
- Xiongjian Rao
- , Xiaotao Duan
- & Wen Yi
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Article
| Open Access
Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding geneSLC12A5, which impair normal synaptic function associated with early-onset epilepsy.
- Tommy Stödberg
- , Amy McTague
- & Manju A. Kurian
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| Open Access
Tyrosine glycosylation of Rho by Yersinia toxin impairs blastomere cell behaviour in zebrafish embryos
Yersinia ruckeri is the source of redmouth disease in fish. Here the authors analysed the Yersiniatoxin Afp18 and show that it acts to inhibit RhoA activation by glycosylating a distinct tyrosine residue inducing a signalling incompetent structural conformation.
- Thomas Jank
- , Stephanie Eckerle
- & Klaus Aktories
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Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies
The glycan patch that covers the HIV-1 envelope protein gp120 can be targeted by broadly neutralizing antibodies. Here, Pritchard et al.show that structural changes in the glycans do not significantly hamper antibody recognition, supporting the glycan patch as a stable target for vaccine design.
- Laura K. Pritchard
- , Daniel I.R. Spencer
- & Max Crispin
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Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation
Polypeptide GalNAc-transferases decorate proteins with dense arrays of O-glycans, which in the case of mucins are essential for their barrier functions. Here the authors present comprehensive structural studies that shed light on the molecular attributes that allow GalNAc-T2 to efficiently carry out dense O-glycosylation.
- Erandi Lira-Navarrete
- , Matilde de las Rivas
- & Ramon Hurtado-Guerrero
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The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold
Two glycosyltransferase folds have been reported, GT-A and GT-B. Here, Zhang et al.report a 1.34 Å resolution structure of a domain of unknown function that adopts a new glycosylation fold, and show that the protein functions as a glycosyltransferase.
- Hua Zhang
- , Fan Zhu
- & Hui Wu
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Sequence-based protein stabilization in the absence of glycosylation
Glycosylation is an essential process for preservation of protein structure and biological activity. Here, the authors show that the introduction of charge clusters containing specific amino-acid sequences can instead be used to control the stability and activity of non-glycosylated proteins.
- Nikki Y. Tan
- , Ulla-Maja Bailey
- & Benjamin L. Schulz
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Unexpected reactivity and mechanism of carboxamide activation in bacterial N-linked protein glycosylation
Oligosaccharyltransferases catalyse the transfer of lipid-anchored glycans onto acceptor asparagine residues in substrate proteins. By assaying chemically modified peptide substrate analogues, Lizak et al. rule out all but one of the currently postulated catalytic mechanisms for this enzyme.
- Christian Lizak
- , Sabina Gerber
- & Kaspar P. Locher
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Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65
GRASP proteins are thought to play a role in maintaining the stacked structure of the Golgi complex. Xiang et al. discover that depletion of GRASPs accelerates Golgi traffic, but reduces the complexity of Golgi protein glycosylation.
- Yi Xiang
- , Xiaoyan Zhang
- & Yanzhuang Wang
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| Open Access
Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Complex diseases such as multiple sclerosis have both genetic and environmental components. This study demonstrates that variants of genes implicated in multiple sclerosis, and alterations in cellular metabolism and vitamin D3 levels, alterN-glycosylation, a post-translational modification causal of the disease in mice.
- Haik Mkhikian
- , Ani Grigorian
- & Michael Demetriou
Dynamic movement of the Golgi unit and its glycosylation enzyme zones