Structural basis for sialoglycan recognition by the immune inhibitory receptor Siglec-10

Sialic acid-binding immunoglobulin-like lectin 10 (Siglec-10) inhibits immune cell function by sensing the presence of sialylated glycoproteins. Here, we determined structures of Siglec-10 bound to sialyllactose (SL) ligands to visualize the molecular recognition events underlying Siglec-10 signaling. The structures reveal that domain 1 (D1) of Siglec-10 engages SL using a non-conserved, selectivity determining CC' loop. Siglec-10 binds α2,3- and α2,6-linked SL with similar affinities despite minor additional contacts between D1 and the α2,3-SL galactose. Homodimerization of Siglec-10 is mediated by a hydrophobic domain 2 (D2) interface, and mutation of this interface ablates cellular binding similarly to mutations in the CC' loop and glycan-binding site. Surprisingly, knockout of the putative Siglec-10 ligand, CD24, did not affect binding to breast cancer cells, indicating that Siglec-10 has a broader-than-expected glycoprotein recognition profile. These findings emphasize how a complex interplay between Siglec-10 multimerization and ligand engagement facilitate cell surface interactions.