2023/04/22 by Edward N. Schmidt, Dimitra Lamprinaki, Kelli A. McCord +24 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Glycosylation and Glycoproteins Research #Lipid Membrane Structure and Behavior #RNA Interference and Gene Delivery
paper · pdf · doi:10.1038/s41467-023-38030-6
openalex publication_date 2023/04/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
Immunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec-glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles. These results demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.