Siglec-7 Undergoes a Major Conformational Change When Complexed with the α(2,8)-Disialylganglioside GT1b

Abstract

The siglecs are a group of mammalian sialic acid binding receptors expressed predominantly in the immune system. The CD33-related siglecs show complex recognition patterns for sialylated glycans. Siglec-7 shows a preference for ␣(2,8)-disialylated ligands and provides a structural template for studying the key interactions that drive this selectivity. We have co-crystallized Siglec-7 with a synthetic oligosaccharide corresponding to the ␣(2,8)-disialylated ganglioside GT1b. The crystal structure of the complex offers a first glimpse into how this important family of lectins binds the structurally diverse gangliosides. The structure reveals that the C-C loop, a region implicated in previous studies as driving siglec specificity, undergoes a dramatic conformational shift, allowing it to interact with the underlying neutral glycan core of the ganglioside. The structural data in combination with mutagenesis studies show that binding of the ganglioside is driven by extensive hydrophobic contacts together with key polar interactions and that the binding site structure is complementary to preferred solution conformations of GT1b.

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

“…A common feature of the binding surface and a notable contribution to its energy is provided by CH-stacking of sugar rings and aromatic protein sidechains (38). Examples most relevant to this study include clostridial neurotoxin in complex with GD1 sugar (39) and sialic acid receptor of immune cells (siglec-7) in complex with GT1b analog (40). In both structures the ganglioside is recognized in a relatively shallow hollow compared with the pronounced groove found in 14G2a.…”

Dendritic Cell Maturation Results in Pronounced Changes in Glycan Expression Affecting Recognition by Siglecs and Galectins

“…In vitro-binding studies have revealed that siglec-7 shows a marked preference for glycoconjugates bearing ␣(2,8)-linked disialic acid (GD3 and GT1b) and branched ␣(2,6)-linked sialic acid (69). The function of siglec-7 on NK cells appear to be related with a down-modulation of the NK killing activity (70), therefore trans interactions between NK cells and DC could serve this function.…”

Sialic Acids on Varicella-Zoster Virus Glycoprotein B Are Required for Cell-Cell Fusion

“…However, Arg-118, which forms an important salt bridge with the negatively charged carboxyl group of SA, is conserved among other Siglec family molecules. The structures of other Siglec family molecules suggest that Arg-118 in MAG is directly involved in binding to SAs (11,12,(47)(48)(49)(50)(51)(52)(53)(54). Therefore, mutation in Arg-118 in MAG seems to have affected the association with SAs rather than the conformation of MAG.…”