Abstract
Siglec-7 is a human CD33-like siglec, and is localised predominantly on human natural killer (NK) cells and monocytes. Siglec-7 is considered to function as an immunoreceptor in a sialic acid-dependent manner. However, the underlying mechanisms linking sialic acid-binding and function remain unknown. Here, to gain new insights into the ligand-binding properties of Siglec-7, we carried out in silico analysis and site-directed mutagenesis, and found a new sialic acid-binding region (site 2 containing R67) in addition to the well-known primary ligand-binding region (site 1 containing R124). This was supported by equilibrium dialysis, STD-NMR experiments, and inhibition analysis of GD3-binding toward Siglec-7 using synthetic sialoglycoconjugates and a comprehensive set of ganglioside-based glycoconjugates. Our results suggest that the two ligand-binding sites are potentially controlled by each other due to the flexible conformation of the C-C′ loop of Siglec-7.
Highlights
Siglecs are sialic acid (Sia)-binding immunoglobulin-like lectins and the majority of them function as transmembrane receptors in the immune system via recognition of Sia residues[1]
Cancer cells have been shown to be protected by Sia on their surface, and a hyper-sialylation state on the cancer cell surface may contribute to escape from natural killer (NK) cell killing[4,9]
Cancer cells were tagged with Sia epitopes with glycopolymers as probes to be targeted by the Siglec-7-expressing NK cells[4,7]
Summary
Siglecs are sialic acid (Sia)-binding immunoglobulin-like lectins and the majority of them function as transmembrane receptors in the immune system via recognition of Sia residues[1]. Siglecs differ from most other mammalian Sia-binding lectins, such as selectins, with respect to the absolute requirement for Sia, but the details of their molecular interactions, including specific natural ligands and ligand-binding mechanisms, remain largely unclear. These are thought to be important for immune cell functions via Sia-binding because disrupting the interactions between Sias and siglecs can alter responses to infection, inflammation, autoimmunity, and cancer[1]. The natural ligands and the underlying recognition mechanisms in which Siglec-7 is involved are still unclear, the high-affinity binding molecules that cluster diSia on the dextran have been developed[3]. Siglec-7 is involved in various biological functions, molecular details of ligand recognition and its potential regulation are still unclear
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