Paradigms for glycan-binding receptors in cell adhesion

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Diverse glycans found on the surfaces of mammalian cells provide a basis for selective adhesion between cells mediated by glycan-specific receptors. Well-understood examples of cell adhesion based on such interactions include selectin-mediated rolling of leukocytes on endothelia. Other receptors with similar selectivity for specific sugar epitopes on cell surfaces are being characterised. However, the simple paradigm of adhesion resulting from receptors on one cell binding to glycans on another cell applies in only a limited number of systems. Instead, glycans and receptor–glycan interactions often modulate adhesion in indirect ways, such as by changing the organisation of cell surface glycoproteins and by antagonising the effect of protein adhesion systems.

Introduction

Ever since the diversity of carbohydrates found on mammalian cell surfaces was recognised, it has been speculated that unique combinations of sugars on individual cells might form the basis for specific cell adhesion events [1]. Proteins able to bind to these glycans present a plausible mechanism for specific recognition events, in which a glycan-binding receptor on one cell interacts with glycans on another cell [2]. However, in many cases, the role of glycan–receptor interaction may be to modulate adhesion rather than to provide a simple bridge between cells (Figure 1). In reviewing the current state of this field, with particular emphasis on progress in the past two years, it is now possible to set high standards for evidence implicating specific receptor–glycan interactions in cell adhesion. The focus of this review will be on mammalian adhesion systems, evaluating which potential adhesion systems are understood in molecular detail and which are supported by convincing physiological evidence about how they function.

Section snippets

Selectins in normal and tumour cell adhesion

The selectins remain the best characterised glycan-binding receptors with well-defined roles in cell adhesion [3, 4]. Experimental approaches ranging from X-ray crystallography to analysis of knockout mice have documented how selective interactions of the selectins with glycoprotein ligands bearing glycans terminating in the sialyl-Lewisx or sialyl-Lewisa tetrasaccharides lead to transient adhesion between leukocytes and endothelia (see Figure 2 for a summary of key glycan structures). Although

Identification of blood cell glycoprotein ligands for DC-SIGN

While the function of the selectins as cell adhesion molecules is now well documented, the importance of other glycan-binding receptors in cell adhesion, as opposed to clearance of pathogens or turnover of serum glycoproteins, remains less well understood. One receptor with a particularly ambiguous dual function is DC-SIGN, which was originally named as a cell adhesion receptor, Dendritic Cell Specific Intercellular adhesion molecule 3-Grabbing Nonintegrin, but which has been more extensively

The scavenger receptor C-type lectin: a novel endothelial receptor that binds Lewisx

The scavenger receptor C-type lectin (SRCL) is a hybrid surface molecule on endothelial cells that, like other scavenger receptors, is organised as extended rod-like domains composed of coiled-coils of α-helices adjacent to collagen-like helices [21, 22]. SRCL is unique amongst the scavenger receptor family in having a carbohydrate-recognition domain at the distal end of the rod domains. Screening of a glycan array with SRCL revealed that it shows unusually selective binding to only a few

A role for galectins in endothelial cell interactions

The galectins are soluble glycan-binding proteins that have been proposed to link cells to each other and to the extracellular matrix by virtue of their bivalency (Figure 1). Some galectins achieve bivalency as a result of dimerisation of a constituent polypeptide that contains a single carbohydrate-recognition domain, while in other galectins two binding sites are adjacent to each other in a single polypeptide [26, 27]. The valance of galectin-3, one of the most extensively studied of the

Polysialic acid and regulation of adhesion in the nervous system

Another known modifier of cell adhesion is polysialic acid, which is attached to a select set of proteins, including the neural cell adhesion molecule (NCAM) [32]. A major effect of polysialylation is to inhibit cell adhesion in general rather than to interfere directly with specific adhesive interactions. Molecular force and other measurements have been used to validate the hypothesis that the charge on extended polysialic acid chains causes increased repulsion between apposing membranes, and

Conclusions

On the basis of the structures of glycan-binding receptors known to be expressed on cell surfaces, it is possible to screen genomes to identify additional receptors (www.imperial.ac.uk/research/animallectins). Such a genomic analysis suggests that the number of human glycan-binding receptors in the three main lectin groups is less than 50 (Table 1). Of these, only a few have at least partially documented roles in cell adhesion even in two of the most complex multicellular situations, the immune

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work was supported by grant 075565 from the Wellcome Trust.

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