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Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications.

ABSTRACT: Mice with null mutations in specific Golgi glycosyltransferases show evidence of glycan compensation where missing carbohydrate epitopes are found on biosynthetically related structures. Repetitive saccharide sequences within the larger glycan structures are functional epitopes recognized by animal lectins. These studies provide the first in vivo support for the existence of a feedback system that maintains and regulates glycan epitope density in cells. Receptor regulation by lectin-glycan interactions and the Golgi provides a mechanism for the adaptation of cell surface receptors and solute transporters in response to environmental cues and intracellular signaling. We suggest that other posttranslational modification systems might have similar conditional features regulated by density-dependent ligand-epitope interactions.

SUBMITTER: Dennis JW

PROVIDER: S-EPMC3617338 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications.

Dennis James W JW Brewer C Fred CF

Molecular & cellular proteomics : MCP 20130201 4

Mice with null mutations in specific Golgi glycosyltransferases show evidence of glycan compensation where missing carbohydrate epitopes are found on biosynthetically related structures. Repetitive saccharide sequences within the larger glycan structures are functional epitopes recognized by animal lectins. These studies provide the first in vivo support for the existence of a feedback system that maintains and regulates glycan epitope density in cells. Receptor regulation by lectin-glycan inter ...[more]

PMID: 23378517

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Project description:Lectin-glycan interactions facilitate inter- and intracellular communication in many processes including protein trafficking, host-pathogen recognition, and tumorigenesis promotion. Specific recognition of glycans by lectins is also the basis for a wide range of applications in areas including glycobiology research, cancer screening, and antiviral therapeutics. To provide a better understanding of the determinants of lectin-glycan interaction specificity and support such applications, this study comprehensively investigates specificity-conferring features of all available lectin-glycan complex structures. Systematic characterization, comparison, and predictive modeling of a set of 221 complementary physicochemical and geometric features representing these interactions highlighted specificity-conferring features with potential mechanistic insight. Univariable comparative analyses with weighted Wilcoxon-Mann-Whitney tests revealed strong statistical associations between binding site features and specificity that are conserved across unrelated lectin binding sites. Multivariable modeling with random forests demonstrated the utility of these features for predicting the identity of bound glycans based on generalized patterns learned from non-homologous lectins. These analyses revealed global determinants of lectin specificity, such as sialic acid glycan recognition in deep, concave binding sites enriched for positively charged residues, in contrast to high mannose glycan recognition in fairly shallow but well-defined pockets enriched for non-polar residues. Focused fine specificity analysis of hemagglutinin interactions with human-like and avian-like glycans uncovered features representing both known and novel mutations related to shifts in influenza tropism from avian to human tissues. As the approach presented here relies on co-crystallized lectin-glycan pairs for studying specificity, it is limited in its inferences by the quantity, quality, and diversity of the structural data available. Regardless, the systematic characterization of lectin binding sites presented here provides a novel approach to studying lectin specificity and is a step towards confidently predicting new lectin-glycan interactions.

Project description:The circadian clock is an endogenous oscillator that drives daily rhythms in physiology, behavior, and gene expression. The underlying mechanisms of circadian timekeeping are cell-autonomous and involve oscillatory expression of core clock genes that is driven by interconnecting transcription-translation feedback loops (TTFLs). Circadian clock TTFLs are further regulated by posttranslational modifications, in particular, phosphorylation. The hippocampus plays an important role in spatial memory and the conversion of short- to long-term memory. Several studies have reported the presence of a peripheral oscillator in the hippocampus and have highlighted the importance of circadian regulation in memory formation. Given the general importance of phosphorylation in circadian clock regulation, we performed global quantitative proteome and phosphoproteome analyses of the murine hippocampus across the circadian cycle, applying spiked-in labeled reference and high accuracy mass spectrometry (MS). Of the 3,052 proteins and 2,868 phosphosites on 1,368 proteins that were accurately quantified, 1.7% of proteins and 5.2% of phosphorylation events exhibited time-of-day-dependent expression profiles. The majority of circadian phosphopeptides displayed abrupt fluctuations at mid-to-late day without underlying rhythms of protein abundance. Bioinformatic analysis of cyclic phosphorylation events revealed their diverse distribution in different biological pathways, most notably, cytoskeletal organization and neuronal morphogenesis. This study provides the first large-scale, quantitative MS analysis of the circadian phosphoproteome and proteome of the murine hippocampus and highlights the significance of rhythmic regulation at the posttranslational level in this peripheral oscillator. In addition to providing molecular insights into the hippocampal circadian clock, our results will assist in the understanding of genetic factors that underlie rhythms-associated pathological states of the hippocampus.

Dataset Information

Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications.

Publications

Density-dependent lectin-glycan interactions as a paradigm for conditional regulation by posttranslational modifications.

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