Journal Article Ahead of print
PubMed: 41747717 DOI: 10.1016/j.str.2026.01.018
Structural basis for sialoglycan recognition by the immune inhibitory receptor Siglec-10.
Structure
Authors: Elliot Medina, Charlotte Mason, Timothy H Tran, Estefanía P Juliá, Qianqian Ming, Leila M Taibi, Patrick Hwu, Roy L Maute, John S Burg, Vincent C Luca
Affiliations
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA.
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
- Chemical Biology Core, Moffitt Cancer Center, Tampa, FL 33612, USA.
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Clinical Science, Moffitt Cancer Center, Tampa, FL 33612, USA.
- Pheast Therapeutics, Redwood City, CA, USA.
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Abstract
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.
MeSH
Cells, N-Acetylneuraminic Acid, Sialic Acid Binding Immunoglobulin-Like Lectins, Glycoproteins, Ligands, Mutation, Lectins