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Advances in understanding N-glycosylation structure, function, and regulation in health and disease.European Journal of Cell Biology 2021N-linked glycosylation is a post-translational modification crucial for membrane protein folding, stability and other cellular functions. Alteration of membrane protein... (Review)
Review
N-linked glycosylation is a post-translational modification crucial for membrane protein folding, stability and other cellular functions. Alteration of membrane protein N-glycans is implicated in wide range of pathological conditions including cancer metastasis, chronic inflammatory diseases, and viral pathogenesis. Even though the roles of N-glycans have been studied extensively, our knowledge of their mechanisms remains unclear due to the lack of detailed structural analysis of the N-glycome. Mapping the N-glycome landscape will open new avenues to explore disease mechanisms and identify novel therapeutic targets. This review discusses the diverse structure of N-linked glycans, the function and regulation of N-glycosylation in health and disease, and ends with a focus on recent approaches to target N-glycans in rheumatoid arthritis and cancer metastasis.
Topics: Glycosylation; Polysaccharides; Protein Processing, Post-Translational
PubMed: 34839178
DOI: 10.1016/j.ejcb.2021.151186 -
Current Biology : CB Apr 2019Eichler introduces the diversity of protein glycosylations and the roles of these modifications in regulating protein function.
Eichler introduces the diversity of protein glycosylations and the roles of these modifications in regulating protein function.
Topics: Glycosylation; Proteins
PubMed: 30939300
DOI: 10.1016/j.cub.2019.01.003 -
Current Opinion in Structural Biology Dec 2022
Topics: Glycosylation; Carbohydrates
PubMed: 36179500
DOI: 10.1016/j.sbi.2022.102468 -
FEMS Microbiology Reviews Jan 2017Glycosylation of proteins is one of the most prevalent post-translational modifications occurring in nature, with a wide repertoire of biological implications. Pathways... (Review)
Review
Glycosylation of proteins is one of the most prevalent post-translational modifications occurring in nature, with a wide repertoire of biological implications. Pathways for the main types of this modification, the N- and O-glycosylation, can be found in all three domains of life-the Eukarya, Bacteria and Archaea-thereby following common principles, which are valid also for lipopolysaccharides, lipooligosaccharides and glycopolymers. Thus, studies on any glycoconjugate can unravel novel facets of the still incompletely understood fundamentals of protein N- and O-glycosylation. While it is estimated that more than two-thirds of all eukaryotic proteins would be glycosylated, no such estimate is available for prokaryotic glycoproteins, whose understanding is lagging behind, mainly due to the enormous variability of their glycan structures and variations in the underlying glycosylation processes. Combining glycan structural information with bioinformatic, genetic, biochemical and enzymatic data has opened up an avenue for in-depth analyses of glycosylation processes as a basis for glycoengineering endeavours. Here, the common themes of glycosylation are conceptualised for the major classes of prokaryotic (i.e. bacterial and archaeal) glycoconjugates, with a special focus on glycosylated cell-surface proteins. We describe the current knowledge of biosynthesis and importance of these glycoconjugates in selected pathogenic and beneficial microbes.
Topics: Archaea; Bacteria; Glycoproteins; Glycosylation; Membrane Proteins; Polysaccharides
PubMed: 27566466
DOI: 10.1093/femsre/fuw036 -
Biochimica Et Biophysica Acta. General... Nov 2021The interaction between hepatitis viruses and host cells is regulated by glycans exposed on the surfaces of human and viruses cells. As the biosynthesis and degradation... (Review)
Review
BACKGROUND
The interaction between hepatitis viruses and host cells is regulated by glycans exposed on the surfaces of human and viruses cells. As the biosynthesis and degradation of human glycoproteins take place at the highest level in the liver, the changes in glycosylation of serum proteins may potentially be useful in the diagnosis of liver pathology. On the other hand, specific alterations in viruses envelope glycans could cause large changes in the entry process of hepatitis viruses into a host cells.
SCOPE OF REVIEW
Unique alterations in glycosylation of specific proteins can be detected in HBV and HCV infected patients especially with confirmed fibrosis/cirrhosis. On the other hand, viral envelope proteins that bind to host cells are glycosylated. These glycosylated proteins play a key role in recognition, binding and penetration of the host cells. In this review we summarized the knowledge about significance of glycosylation for viral and host factors.
MAJOR CONCLUSIONS
Glycosylation changes in single serum glycoproteins are noticed in the sera of patients with viral hepatitis. However, a more specific biomarker for the diagnosis of chronic hepatitis than that of a single glycosylated molecule is systemic investigation of complete set of glycan structures (N-glycome). Glycans play important roles in the viral biology cycle especially as a connecting element with host receptors.
GENERAL SIGNIFICANCE
The interaction between virus glycoproteins and cellular receptors, which are also glycoproteins, determines the possibility of virus penetration into host cells. Therefore these glycans can be the targets for the developing of novel treatment strategies of viral hepatitis.
Topics: Glycosylation; Hepatitis, Viral, Human; Humans
PubMed: 34474116
DOI: 10.1016/j.bbagen.2021.129997 -
Biomolecules Sep 2022This article is part of the Special Issue Glycosylation-The Most Diverse Post-Translational Modification [...].
This article is part of the Special Issue Glycosylation-The Most Diverse Post-Translational Modification [...].
Topics: Glycosylation; Protein Processing, Post-Translational
PubMed: 36139152
DOI: 10.3390/biom12091313 -
Nature Communications Feb 2023Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of...
Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.
Topics: Animals; Glycosylation; SARS-CoV-2; COVID-19; Glycoproteins; Polysaccharides
PubMed: 36804936
DOI: 10.1038/s41467-023-36598-7 -
The Biochemical Journal Sep 2022Eukaryotic protein glycosylation is mediated by glycosyl- and oligosaccharyl-transferases. Here, we describe how African trypanosomes exhibit both evolutionary...
Eukaryotic protein glycosylation is mediated by glycosyl- and oligosaccharyl-transferases. Here, we describe how African trypanosomes exhibit both evolutionary conservation and significant divergence compared with other eukaryotes in how they synthesise their glycoproteins. The kinetoplastid parasites have conserved components of the dolichol-cycle and oligosaccharyltransferases (OSTs) of protein N-glycosylation, and of glycosylphosphatidylinositol (GPI) anchor biosynthesis and transfer to protein. However, some components are missing, and they process and decorate their N-glycans and GPI anchors in unique ways. To do so, they appear to have evolved a distinct and functionally flexible glycosyltransferases (GT) family, the GT67 family, from an ancestral eukaryotic β3GT gene. The expansion and/or loss of GT67 genes appears to be dependent on parasite biology. Some appear to correlate with the obligate passage of parasites through an insect vector, suggesting they were acquired through GT67 gene expansion to assist insect vector (tsetse fly) colonisation. Others appear to have been lost in species that subsequently adopted contaminative transmission. We also highlight the recent discovery of a novel and essential GT11 family of kinetoplastid parasite fucosyltransferases that are uniquely localised to the mitochondria of Trypanosoma brucei and Leishmania major. The origins of these kinetoplastid FUT1 genes, and additional putative mitochondrial GT genes, are discussed.
Topics: Glycosylation; Glycosylphosphatidylinositols; Glycosyltransferases; Trypanosoma; Trypanosoma brucei brucei
PubMed: 36066312
DOI: 10.1042/BCJ20210778 -
Frontiers in Endocrinology 2023As a metabolic disease, diabetes often leads to health complications such as heart failure, nephropathy, neurological disorders, and vision loss. Diabetic retinopathy...
INTRODUCTION
As a metabolic disease, diabetes often leads to health complications such as heart failure, nephropathy, neurological disorders, and vision loss. Diabetic retinopathy (DR) affects as many as 100 million people worldwide. The mechanism of DR is complex and known to impact both neural and vascular components in the retina. While recent advances in the field have identified major cellular signaling contributing to DR pathogenesis, little has been reported on the protein post-translational modifications (PTM) - known to define protein localization, function, and activity - in the diabetic retina overall. Protein glycosylation is the enzymatic addition of carbohydrates to proteins, which can influence many protein attributes including folding, stability, function, and subcellular localization. -linked glycosylation is the addition of sugars to an oxygen atom in amino acids with a free oxygen atom in their side chain (i.e., threonine, serine). To date, more than 100 congenital disorders of glycosylation have been described. However, no studies have identified the retinal -linked glycoproteome in health or disease. With a critical need to expedite the discovery of PTMomics in diabetic retinas, we identified both global changes in protein levels and the retinal -glycoproteome of control and diabetic mice.
METHODS
We used liquid chromatography/mass spectrometry-based proteomics and high throughput screening to identify proteins differentially expressed and proteins differentially -glycosylated in the retinas of wildtype and diabetic mice.
RESULTS
Changes in both global expression levels of proteins and proteins differentially glycosylated in the retinas of wild-type and diabetic mice have been identified. We provide evidence that diabetes shifts both global expression levels and -glycosylation of metabolic and synaptic proteins in the retina.
DISCUSSION
Here we report changes in the retinal proteome of diabetic mice. We highlight alterations in global proteins involved in metabolic processes, maintaining cellular structure, trafficking, and neuronal processes. We then showed changes in -linked glycosylation of individual proteins in the diabetic retina.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Proteomics; Diabetic Retinopathy; Retina; Glycosylation; Proteome
PubMed: 37693346
DOI: 10.3389/fendo.2023.1229089 -
Malaria Journal Oct 2015Glycoconjugates are important mediators of host-pathogen interactions and are usually very abundant in the surface of many protozoan parasites. However, in the... (Review)
Review
Glycoconjugates are important mediators of host-pathogen interactions and are usually very abundant in the surface of many protozoan parasites. However, in the particular case of Plasmodium species, previous works show that glycosylphosphatidylinositol anchor modifications, and to an unknown extent, a severely truncated N-glycosylation are the only glycosylation processes taking place in the parasite. Nevertheless, a detailed analysis of the parasite genome and the recent identification of the sugar nucleotide precursors biosynthesized by Plasmodium falciparum support a picture in which several overlooked, albeit not very prominent glycosylations may be occurring during the parasite life cycle. In this work, the authors review recent developments in the characterization of the biosynthesis of glycosylation precursors in the parasite, focusing on the outline of the possible fates of these precursors.
Topics: Carbohydrate Metabolism; Glycosylation; Metabolic Networks and Pathways; Plasmodium falciparum
PubMed: 26520586
DOI: 10.1186/s12936-015-0949-z