Disease relevance of Glycosylation

• Here, we show that the chemokine receptor CCR5, a principal HIV-1 coreceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines [1].
• Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken syndrome) is the prototype of a class of genetic multisystem disorders characterized by defective glycosylation of glycoconjugates [2].
• Evidence is presented that synthesis, glycosylation, processing and membrane transport of the env polypeptide occurred without other HTLV-III gene functions; the env protein was recognized by sera from unrelated AIDs patients; and a single vaccination with the infectious recombinant vaccinia virus induced antibodies to gp120 in mice [3].
• Rhesus monkeys were infected with mutant forms of simian immunodeficiency virus lacking dual combinations of the 4th, 5th and 6th sites for N-linked glycosylation in the external envelope glycoprotein of the virus [4].
• Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG [5].

Psychiatry related information on Glycosylation

• The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid [6].
• These findings suggest that altered AChE glycosylation in CJD may be a consequence of the general perturbation of the glycosylation machinery that affects prion protein, as well as other proteins [7].
• Transferrin exhibits heterogeneity in glycosylation characteristic of pathological changes in alcohol abuse and congenital disorders in glycosylation [8].
• Changes in the glycosylation pattern of circulating gonadotropins after acute administration of gonadotropin-releasing hormone in patients with anorexia nervosa [9].
• Studies of this major cell surface glycoprotein have provided insight into the biochemical mechanisms of cellular adhesion, morphology, and social interaction and provide an approach to analyze the dynamics and regulation of protein synthesis, glycosylation, secretion, and turnover [10].

High impact information on Glycosylation

• Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation [11].
• We infer that beta cell glucose-transporter glycosylation mediates a link between diet and insulin production that typically suppresses the pathogenesis of type 2 diabetes [12].
• Remarkably, the induction of diabetes by chronic ingestion of a high-fat diet is associated with reduced GlcNAcT-IV expression and attenuated Glut-2 glycosylation coincident with Glut-2 endocytosis [12].
• Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required [13].
• Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency [14].

Chemical compound and disease context of Glycosylation

• The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications [15].
• Parasitized cells bound to Chinese hamster ovary (CHO) cells and C32 melanoma cells in a chondroitin sulfate-dependent manner, whereas glycosylation mutants lacking chondroitin sulfate A (CSA) supported little or no binding [16].
• Erythrocyte membranes from three patients with hemolytic anemia showed reduced incorporation of tritium from [3H]-borohydride, indicating decreased nonenzymatic glycosylation [17].
• Treatment of human SH-SY5Y neuroblastoma cells with tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target genes of the unfolded protein response [18].
• Using human melanoma cells stably transfected with CD44 N-linked glycosylation site-specific mutants, we show that integrity of five potential N-linked glycosylation sites within the hyaluronate recognition domain of CD44 is critical for hyaluronate binding [19].

Biological context of Glycosylation

• The deduced amino acid sequence suggests that mdr is a membrane glycoprotein which includes six pairs of transmembrane domains and a cluster of potentially N-linked glycosylation sites near the amino terminus [20].
• Posttranslational modification of alpha-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation [13].
• These may include elevated basal TSH values, which may transiently increase to greater than 10 mU/liter, blunted TSH response to TRH, diminished or absent TSH diurnal rhythm, altered TSH glycosylation, and impaired TSH and TRH clearance rates [21].
• Molecular modeling based on the recently solved CR2 structure in complex with C3d reveals that this glycosylation interferes with receptor dimerization [22].
• The Golgi apparatus, in turn, has a central role in protein sorting and glycosylation within the eukaryotic secretory pathway [23].

Anatomical context of Glycosylation

• These data indicate that normal glycosylation of T25 glycoprotein is probably essential for the molecule to be incorporated into the plasma membrane and expressed on the cell surface [24].
• Mouse H-2Dd histocompatibility antigen was correctly assembled in the microsomal membranes, and transmembrane insertion of the nascent chain was accompanied by glycosylation and cleavage of the signal sequence H-2Kd antigens, synthesized in vivo, comprised a transmembrane glycoprotein and an unglycosylated protein in the cytoplasm [25].
• Band III was found to insert into dog pancreatic microsomes in a cotranslational manner; in synchronized translation studies microsomes could be added as late as the time when the hydrophilic NH2-terminal half of the protein had been synthesized and still allow normal transmembrane insertion and glycosylation [26].
• Glycoprotein synthesis and inhibition of glycosylation by tunicamycin in preimplantation mouse embryos: compaction and trophoblast adhesion [27].
• Chloroquine and ammonium chloride prevent terminal glycosylation of immunoglobulins in plasma cells without affecting secretion [28].

Associations of Glycosylation with chemical compounds

• Tunicamycin specifically inhibits glycosylation of asparaginyl residues of glycoproteins [27].
• Reduced temperature prevents transfer of a membrane glycoprotein to the cell surface but does not prevent terminal glycosylation [29].
• The sequence predicts a cytoplasmic domain of 50 amino acids at the COOH terminus, followed in order by a membrane-spanning region of 27 hydrophobic amino acids and an externally disposed stretch of 42 amino acids, that is rich in serine and threonine residues and appears to be the site of O-linked glycosylation [30].
• Glycosylation of chromosomal proteins: localization of O-linked N-acetylglucosamine in Drosophila chromatin [31].
• Treatment with monensin caused accumulation in the cell of a form of G1 with partial sensitivity toward endo H, suggesting that monensin may act to inhibit the glycosylation process directly [32].

Gene context of Glycosylation

• Additional experiments showed that the expression and function of CD59 are both glycosylation independent [33].
• These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6 [34].
• Here we show that vIL-6 is N-linked glycosylated at N78 and N89 and demonstrate that N-linked glycosylation at site N89 of vIL-6 markedly enhances binding to gp130, signaling through the JAK1-STAT1/3 pathway and functions in a cytokine-dependent cell proliferation bioassay [34].
• Defects in DPM1 define a new glycosylation disorder, CDG-Ie [35].
• A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If) [36].

Analytical, diagnostic and therapeutic context of Glycosylation

• Abnormalities in the glycosylation of immunoglobulin heavy chain and an h-2 transplantation antigen in a mouse myeloma mutant [37].
• Western blot analysis showed that the levels of both mutant proteins in the oocyte were comparable to wild-type SGLT1, but no complex glycosylation was detected [38].
• This mucin is synthesized as a precursor protein of approximately 600 kilodaltons, which, after glycosylation, is secreted as a glycoprotein with an apparent molecular weight of 550 kilodaltons on SDS-PAGE [39].
• Disruption of N-linked glycosylation of tPA by either site-directed mutagenesis or tunicamycin treatment resulted in reduced levels of secretion and increased association with BiP [40].
• Sequence analysis of the cDNA clone revealed that the Ly-6E.1 protein consists of a 26-amino acid leader followed by a 108-residue, cysteine-rich, core protein with no N-linked glycosylation sites [41].

References