The cell surface is the platform for presentation of biochemical signals that are required for intercellular communication. Their profile necessarily needs to be responsive to internal and external ...factors in a highly dynamic manner. The structural features of the signals must meet the criterion of high-density information coding in a minimum of space. Thus, only biomolecules that can generate many different oligomers (‘words’) from few building blocks (‘letters’) qualify to meet this challenge. Examining the respective properties of common biocompounds that form natural oligo- and polymers comparatively, starting with nucleotides and amino acids (the first and second alphabets of life), comes up with sugars as clear frontrunner. The enzymatic machinery for the biosynthesis of sugar chains can indeed link monosaccharides, the letters of the third alphabet of life, in a manner to reach an unsurpassed number of oligomers (complex carbohydrates or glycans). Fittingly, the resulting glycome of a cell can be likened to a fingerprint. Conjugates of glycans with proteins and sphingolipids (glycoproteins and glycolipids) are ubiquitous in Nature. This implies a broad (patho)physiologic significance. By looking at the signals, at the writers and the erasers of this information as well as its readers and ensuing consequences, this review intends to introduce a broad readership to the principles of the concept of the sugar code.
An introduction to the sugar code Gabius, Hans-Joachim; Roth, Jürgen
Histochemistry and cell biology,
02/2017, Letnik:
147, Številka:
2
Journal Article
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Carbohydrates have physiological importance far beyond their roles as source of energy (glycolysis) and activated hydrogen for synthesis (pentosephosphate pathway) or as constituent of the backbone ...of nucleic acids and of cell wall polysaccharides. The extent of compositional and structural variability of their oligomers (glycans) is unsurpassed in Nature due to the unique property of independently combining the following parameters with sequence: anomeric status, linkage positions, ring size, addition of branches and site-specific introduction of substitutions. The monosaccharides (letters of the third alphabet of life) thus generate ‘words’ (signals) of high-density coding capacity. These ‘words’ are part of the glycans on proteins and lipids, and the glycome represented by these ‘words’ in their entirety has cell type-dependent features. The often limited intramolecular flexibility of oligosaccharides along with an abundance of contact points for intermolecular interactions is ideal for binding processes. Glycan-based ‘words’ can thus be ‘read,’ and their message translated into cellular effects by receptors called lectins. This journal’s special issue covers central aspects of the concept of the sugar code.
Ubiquitous occurrence in Nature, abundant presence at strategically important places such as the cell surface and dynamic shifts in their profile by diverse molecular switches qualifies the glycans ...to serve as versatile biochemical signals. However, their exceptional structural complexity often prevents one noting how simple the rules of objective-driven assembly of glycan-encoded messages are. This review is intended to provide a tutorial for a broad readership. The principles of why carbohydrates meet all demands to be the coding section of an information transfer system, and this at unsurpassed high density, are explained. Despite appearing to be a random assortment of sugars and their substitutions, seemingly subtle structural variations in glycan chains by a sophisticated enzymatic machinery have emerged to account for their specific biological meaning. Acting as 'readers' of glycan-encoded information, carbohydrate-specific receptors (lectins) are a means to turn the glycans' potential to serve as signals into a multitude of (patho)physiologically relevant responses. Once the far-reaching significance of this type of functional pairing has become clear, the various modes of spatial presentation of glycans and of carbohydrate recognition domains in lectins can be explored and rationalized. These discoveries are continuously revealing the intricacies of mutually adaptable routes to achieve essential selectivity and specificity. Equipped with these insights, readers will gain a fundamental understanding why carbohydrates form the third alphabet of life, joining the ranks of nucleotides and amino acids, and will also become aware of the importance of cellular communication via glycan-lectin recognition.
Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system with unknown etiology. Currently approved disease-modifying treatment modalities ...are immunomodulatory or immunosuppressive. While the applied drugs reduce the frequency and severity of the attacks, their efficacy to regenerate myelin membranes and to halt disease progression is limited. To achieve such therapeutic aims, understanding biological mechanisms of remyelination and identifying factors that interfere with remyelination in MS can give respective directions. Such a perspective is given by the emerging functional profile of galectins. They form a family of tissue lectins, which are potent effectors in processes as diverse as adhesion, apoptosis, immune mediator release or migration. This review focuses on endogenous and exogenous roles of galectins in glial cells such as oligodendrocytes, astrocytes and microglia in the context of de- and (re)myelination and its dysregulation in MS. Evidence is arising for a cooperation among family members so that timed expression and/or secretion of galectins-1, -3 and -4 result in modifying developmental myelination, (neuro)inflammatory processes, de- and remyelination. Dissecting the mechanisms that underlie the distinct activities of galectins and identifying galectins as target or tool to modulate remyelination have the potential to contribute to the development of novel therapeutic strategies for MS.
What is the Sugar Code? Gabius, Hans‐Joachim; Cudic, Maré; Diercks, Tammo ...
Chembiochem : a European journal of chemical biology,
July 5, 2022, Letnik:
23, Številka:
13
Journal Article
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A code is defined by the nature of the symbols, which are used to generate information‐storing combinations (e. g. oligo‐ and polymers). Like nucleic acids and proteins, oligo‐ and polysaccharides ...are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins ‘read’ the glycan‐encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C−H/π‐interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan‐lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post‐binding events. They give an entry to the glycan vocabulary its functional, often context‐dependent meaning(s), hereby building the dictionary of the sugar code.
Information coding by sugars: Letting symbols convey information comes in many forms such as the QR code. We explain that sugars are an ideal alphabet of life. They form an unsurpassed size of bio‐vocabulary. It is read and translated by a matching diversity of sugar receptors (lectins) so that establishing a dictionary for the glyco‐vocabulary is now in progress. The given QR code directs you to our review on the sugar code.
Functional pairing of cellular glycoconjugates with tissue lectins is a highly selective process, whose determinative factors have not yet been fully delineated. Glycan structure and modes of ...presentation, that is, its position and density, can contribute to binding, as different members of a lectin family can regulate degrees of responsiveness to these factors. Using a peptide repeat sequence motif of the glycoprotein mucin-1, the principle of introducing synthetic (glyco)peptides with distinct variations in these three parameters to an array-based screening of tissue lectins is illustrated. Interaction profiles of seven adhesion/growth-regulatory galectins cover the range from intense signals with core 2 pentasaccharides and core 1 binding for galectins-3 and -5 to a lack of binding for galectin-1 and also the galectin-related protein, which was included as a negative control. Remarkably, the two tandem-repeat-type galectins-4 and -8 were distinguished by core 1 sialylation, as the two separated domains were. These results encourage further synthetic elaboration of the glycopeptide library and testing of the network of natural galectins and rationally engineered variants of the lectins.
Glycan‐protein interactions play an important role in a broad range of physiological processes, raising interest to elucidate the structural interplay. Yet, their dynamic nature limits the analysis ...by crystallography, whereas NMR spectroscopy suffers from the low 1H dispersion of glycans. Therefore, their sparse fluorination and NMR screening by 1D Saturation Transfer Difference with relay to 19F (STDreF) was previously proposed to exploit the superior dispersion in 19F NMR spectroscopy. A new 2D STD‐TOCSYreF experiment is presented here that enables comprehensive epitope mapping of fluorinated glycans by combining the spectral resolution of 19F with the spatial resolution and coverage of 1H. For an illustration, the 2‐deoxy‐2‐fluoro derivative of the N‐glycan core trimannoside was synthesised and its recognition of Pisum sativum agglutinin by either of the two terminal mannose residues was confirmed. Going beyond the crystallographic information, the 2D STD‐TOCSYreF spectrum moreover visualised collateral contacts from the branching mannose and allowed to assess the ratio of both co‐existing binding modes through the α1,3‐ (67 %) and α1,6‐linked (33 %) terminal mannose moieties.
Glycan‐lectin recognition is involved in many (patho)physiological processes. Strategic 19F incorporation into the ligand enables comprehensive epitope mapping for lectin binding by the new 2D STD‐TOCSYreF (saturation transfer difference TOCSY with relay to 19F) NMR experiment, which combines the superior spectral resolution of 19F with the vast spatial resolution and coverage of 1H.
Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. ...Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.
Synopsis
Chemokines and galectins are simultaneously upregulated during inflammation and mediate leukocyte recruitment. A systematic screen now demonstrates their physical interaction as heterodimers, identifying several novel interacting pairs.
Chemokines and galectins can engage in cross talk by pairing, as exemplified by galectin‐3 and CXCL12.
The association of CXCL12 with galectin‐3 appears to have potential for modulating chemokine activity.
Galectin‐3 inhibits CXCL12‐induced chemotaxis of leukocytes and their recruitment to inflammation sites.
Galectin‐3 attenuates CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex.
Chemokines and galectins are simultaneously upregulated during inflammation and mediate leukocyte recruitment. A systematic screen now demonstrates their physical interaction as heterodimers, identifying several novel interacting pairs.
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