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- Title
Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket.
- Authors
Schmidt, Edward N.; Lamprinaki, Dimitra; McCord, Kelli A.; Joe, Maju; Sojitra, Mirat; Waldow, Ayk; Nguyen, Jasmine; Monyror, John; Kitova, Elena N.; Mozaneh, Fahima; Guo, Xue Yan; Jung, Jaesoo; Enterina, Jhon R.; Daskhan, Gour C.; Han, Ling; Krysler, Amanda R.; Cromwell, Christopher R.; Hubbard, Basil P.; West, Lori J.; Kulka, Marianne
- Abstract
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. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer. Here, the authors combine a variety of chemical biology techniques to demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.
- Subjects
GLYCOLIPIDS; EXTRACELLULAR vesicles; CHEMICAL biology; MAST cells; BILAYER lipid membranes; B cells; LIPOSOMES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-38030-6