Structural implications of Siglec‐5 mediated sialo‐glycan recognition

Sialic acid Ig‐like binding lectins (Siglecs) are important mediators of recognition and signaling events among myeloid cells. Through recognition of sialylated carbohydrates on target cells, Siglecs participate in the negative regulation of immune response by inhibiting apoptosis, cell proliferation and NK‐mediated cell lysis. Whereas the cellular function of several Siglecs has been extensively investigated, the structural basis of their carbohydrate specificity remains poorly understood. To further understand the ligand‐binding preferences of the Siglec family of lectins and their biological implications, we have expressed and crystallized two N‐terminal V‐ and C2‐set Ig domains of human Siglec‐5. Through structural studies of Siglec‐5 and its complexes with two carbohydrate ligands, we examined the glycosidic linkage preference of Siglec‐5, the contribution of the C2‐type domain to the binding of carbohydrate ligands and the role of the inter ‐domain disulfide bond, an unusual and highly conserved feature among Siglec family members. These structural observations in conjunction with surface plasmon resonance binding assays provide mechanistic insights into the Siglec‐specific carbohydrate recognition and suggest that Siglec‐5 and other Siglec receptors are more promiscuous in sialo‐glycan recognition than previously appreciated.