Less than a decade ago, the cloning of three seemingly disparate vascular cell surface molecules uncovered the selectin family of receptors that are now known to mediate critical cell-cell interactions in processes such as leukocyte trafficking, thrombosis, acute and chronic inflammation, and ischemia-reperfusion injury (1–15). L-, E-, and P-selectin are type-1 membrane glycoproteins sharing a similar structure, comprising an NH2-terminal calcium-dependent “C type” lectin domain, an EGF-like domain, variable numbers of short consensus repeats domains, a single-pass transmembrane-domain, and a cytosolic carboxyl terminal tail. Abundant evidence indicates that selectins recognize specific carbohydrate ligands. Extensive studies involving mutagenesis, domain swapping, antibody inhibition, etc., have helped to define the functional domains of the selectins. It appears that selectin recognition of carbohydrate ligands involves primarily the amino-terminal C-type lectin domain, influenced to a substantial extent by the EGF-like domain, and to a much lesser degree by the short consensus repeats (1–20). As with most other adhesion receptors, it is also evident that selectins are signaling molecules. This perspective focuses on one of the most puzzling and controversial aspects of selectin biology—the structure of the natural ligands recognized by these receptors.

Mammalian lectin domains typically recognize specific oligosaccharide sequences with considerable selectivity, but relatively low affinity. Thus, for example, the cation-independent M6P receptor (CI-M6PR) recognizes mannose 6-phosphate 1-2 linked to another mannose (21), CD22 recognizes an 2-6–linked sialic acid residue attached to Gal 1-4GlcNAc (22), and the selectins share the ability to recognize the tetrasaccharide sialyl-Lewisx (SLex) 1 and its isomer sialyl-Lewisa. In the first two instances, Kd values for the basic recognition sequence are in the low micromolar range, and higher affinity