Discovery and characterization of vertebrate sialoglycan-binding proteins

All known life forms feature a dense ensemble of cell surface and extracellular glycans. In vertebrates this includes a high density of sialic acids (Sias), a family of acidic sugars typically capping glycans of cell surface or secreted glycoproteins and glycolipids. Since Sia was found to be the receptor for the influenza virus, many other pathogens have since been shown to recognize specific host sialoglycans as targets for their hemagglutinins, adhesins and toxins, often with remarkable specificity and high affinity/avidity. Other pathogens have evolved diverse mechanisms to evade host immunity by 'molecular mimicry' of host sialoglycans. Sialic acids also act as "biological masks", preventing access to underlying structures. Until the late 1970s, it was assumed that endogenous sialoglycan-binding proteins (SGBPs) did not exist in vertebrates. Several such vSGBPs have since been discovered, characterized by distinct sialoglycan specificities but generally low affinity. Markedly different rates of evolution and "Red Queen" effects likely explain this striking difference from the high specificity and affinity/avidity of numerous microbial SGBPs (mSGBPs). Nevertheless, these vSGBPs play important roles in normal development, physiology and disease conditions, with implications for human evolution. This review describes the discovery and characterization of vSGBPs. Most are previously known proteins, and their sialoglycan recognition had been discovered serendipitously. Thus, we may be seeing the 'tip of an iceberg' with many more such proteins to be discovered. We also emphasize recent studies showing that SGBP properties are markedly affected by competing endogenous Sialomes, such that in vitro studies may need to be re-visited, under conditions present in vivo.