3D Modeling of a Natural Killer Receptor, Siglec-7: Critical Amino Acids for Glycan-Binding and Cell Death-Inducing Activity

Siglecs comprise a family of sialic acid-binding Ig-like lectins, expressed mainly on hematopoietic cells (O'Reilly and Paulson 2010; Angata 2006; Crocker, Paulson et al. 2007). More than ten Siglecs of human orgin have been cloned, all of which bind sialoglycans. Structural commonalities include an extracellular N-terminal V-set Ig-like domain, a sialoglycan-binding domain followed by variable numbers of C2-set Ig-like domains, a transmembrane domain, and a cytoplasmic signaling domain. Each member is expressed in a cell-specific manner, e.g., Siglec-1 on macrophages, Sigelc-2 on B cells, Siglec-7 on natural killer cells, and Siglec-9 on myelocytic cells. Even though Siglecs bind terminal sialic acids on glycoconjugates, each member preferentially binds different oligosaccharide ligands. The nature of a specific sialic acid, its linkage to substituted sugars, and underlying neutral oligosaccharides can all influence Siglec recognition (see Table 1). For instance, Siglec-1 binds a terminal NeuAc2-3Gal, but not a NeuAc2-6Gal residue. In contrast, Siglec-2 preferentially binds a terminal NeuAc26Gal residue (Blixt, Collins et al. 2003; Blixt, Han et al. 2008). Siglec-9 binds both of the structures equally. Siglec-7 binds tumor-associated glycans such as so-called “melanoma antigen” (disialyl glycan; NeuAc2-8NeuAc2-3Gal) and the branched 2-6sialyl glycan (Gal1-3[NeuAc2-6]GlcNAc) (Yamaji, Teranishi et al. 2002; Miyazaki, Ohmori et al. 2004). The binding of Siglec-7 to unique sialoglycans may be associated with tumor recognition by NK cells. In this context, it is notable that antibody-crosslinking of Siglec-7 on NK cells attenuates the cytotoxicity of NK cells against FcR+ P815 murine mastocytoma cells (Nicoll,  Corresponding author