Natural ligands for CD33-related Siglecs?

Finding natural ligands involved in protein–protein interactions is relatively easy, and false-positives are rare. In contrast, the natural ligands for glycan-binding proteins (GBPs) can be quite elusive, and artifacts are common. For example, it took almost 10 years from the detection of P-selectin's glycan binding properties (Moore et al. 1991) to reach the definitive conclusion that a certain specific posttranslationally modified form of the polypeptide PSGL-1 was the functionally relevant natural ligand for this GBP (Epperson et al. 2000). There are many reasons for such difficulties, including the fact that glycan binding is often of relatively low affinity and relies on multivalency to achieve adequate avidity, as well as the complexities of local rebinding effects such as the recently described “jump and bind” mechanisms for lectin–mucin interactions (Dam and Brewer 2008). Meanwhile, investigators continue to incorrectly state that “PSGL-1 is the ligand for P-selectin,” without realizing that while the PSGL-1 polypeptide backbone is expressed in many cell types (Laszik et al. 1996), it is only the correctly sialylated, fucosylated, and tyrosine-sulfated form found in certain cells that can function as a P-selectin ligand. In this regard, an excellent prior suggestion is to define the ligand as the glycan(s) bound by the GBP, the protein or lipid to which the glycan(s) are bound as the “carrier,” and the composite of the glycan and the carrier as the “counter–receptor” (Crocker and Feizi 1996) (see Notes).